CN1980710B - Substituted azepine derivatives as serotonin receptor modulators - Google Patents
Substituted azepine derivatives as serotonin receptor modulators Download PDFInfo
- Publication number
- CN1980710B CN1980710B CN2005800209872A CN200580020987A CN1980710B CN 1980710 B CN1980710 B CN 1980710B CN 2005800209872 A CN2005800209872 A CN 2005800209872A CN 200580020987 A CN200580020987 A CN 200580020987A CN 1980710 B CN1980710 B CN 1980710B
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- CN
- China
- Prior art keywords
- azepine
- tetrahydrochysene
- thieno
- bromo
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract
The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are hexahydroazepinoindole and octahydroazepinoindole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).
Description
Invention field
The present invention relates generally to a series of compounds, relates to the pharmaceutical composition that comprises described compound, relates to described compound and compositions as the purposes of therapeutic agent.In particular, compound of the present invention is six hydrogen thieno azepines and octahydro thieno azepine compound.These compounds are 5-hydroxytryptamine receptor (5-HT) parts, can be used for the treatment needs and regulate 5-hydroxytryptamine receptor (5-HT) active disease, disease and situation (for example addiction, anxiety neurosis, depression and obesity).
Background of invention
Pointed out that 5-hydroxy tryptamine involves many central nervous system's of originating from disease, disease and situation, for example comprised disease, disease and the situation relevant with schizophrenia with sleep, diet, pain perception, body temperature control, controlling of blood pressure, depression, anxiety, addiction.5-hydroxy tryptamine also plays important effect in peripheral-system such as gastronintestinal system, found that it can mediate the multiple effects such as contraction, secretion and electric physiology in these systems.
Because 5-hydroxy tryptamine is widely distributed in vivo, need to affect the medicine of serotonergic system.Specifically, the agonist of serotonergic system, partial agonist and antagonist are significant to the treatment of various diseases, and described disease comprises the vomiting that anxiety neurosis, depression, hypertonicity, migraine, obesity, obsession, schizophrenia, autism, neurodegenerative disease (for example alzheimer disease, parkinson disease and Huntington Chorea) and chemotherapy cause.
Primary categories (the 5-HT of 5-hydroxytryptamine receptor
1-7) comprising the independent receptor of 1-7 class, they are by Official Classification.Referring to Glennon etc., Neuroscience and Behavioral Reviews, 1990,14,35 and D.Hoyer etc., Pharmacol Rev.1994,46,157-203.
For example, 5-HT
2Receptor family comprises 5-HT
2a, 5-HT
2bAnd 5-HT
2cHypotype, they are according to primary structure, secondary messager system and interaction property classification.All these three kinds of 5-HT
2Hypotype is all g protein coupled receptor, activates the phospholipase C as main Transduction Mechanism, contains seven-transmembrane domain structure.Three kinds of 5-HT
2Hypotype is distributed with obvious difference in mammal.5-HT
2bReceptor and 5-HT
2aReceptor extensively is distributed in peripheral nervous system, 5-HT
2aAlso be found in brain.5-HT
2cReceptor only is found in the central nervous system, expresses at the many regional camber of human brain.Referring to G.Baxter etc., Trends in Pharmacol.Sci1995,16,105-110.
With 5-HT
2aHypotype and some effects associate, and comprise that vasoconstriction, platelet aggregation, bronchus are dwindled and some CNS effect, with 5-HT
2cHypotype is associated to some diseases, comprises depression, anxiety neurosis, obsession, addiction, Panic disorder, phobia, psychiatric syndrome and obesity.To 5-HT
2bThe pharmacotoxicological effect of receptor is known little about it.Referring to F.Jenck etc., Exp.Opin.Invest.Drugs, 1998,7,1587-1599; M.Bos etc., J.Med.Client., 1997,40,2762-2769; J.R.Martin etc., The Journal ofPharmacology and Experimental Therapeutics, 1998,286,913-924; S.M.Bromidge etc., 1.Med.Chem., 1998,41,1598-1612; G.A.Kennett, Drugs, 1998, Isosorbide-5-Nitrae, 456-470; With A.Dekeyne etc., Neurophannacology, 1999,38,415-423.
WO 93/13105 discloses thiophene derivant, and United States Patent (USP) discloses thiophene derivant, furan derivatives and azole derivatives No. 4414225, and WO 96/12201 discloses furan derivatives.
Summary of the invention
The present invention relates to following formula: compound:
Wherein X is S, O or NR
5
R
1And R
2Independently be selected from H, halogen, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, C
1-8Thiazolinyl, perhaloalkyl radical, CN, OR
5, SR
5, N (R
5)
2, CON (R
5)
2, NR
5COR
5, NR
5CO
2R
5, SO
2N(R
5)
2, NR
5SO
2R
5, aryl and heteroaryl, wherein said aryl or heteroaryl can be chosen wantonly by maximum three substituent groups that are selected from alkyl, halogen and alkoxyl and replace, perhaps R
1And R
2Form together 5 yuan or 6 rings;
R
3Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5, CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
3aH, perhaps R
3And R
3aBe together-CH
2CH
2-, perhaps R
2And R
3Form 5 yuan or 6 rings;
R
4Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5, CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
4aH, perhaps R
3And R
3aBe together-CH
2CH
2-;
R
5Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, aryl, heteroaryl and perhaloalkyl radical, perhaps R
5Form hetero-aromatic ring together with atom that it connects.
Another embodiment of the invention provides the pharmaceutical composition that comprises formula (I) compound or the acceptable salt of its medicine and drug acceptable carrier.
Another embodiment of the present invention provides the method for disease, disease and/or situation in treatment mammal (for example animals or humans), wherein involves 5-HT
2cReceptor needs to regulate 5-HT
2cFunction.Described method comprises formula (I) compound or the acceptable salt of its medicine that gives described mammal treatment effective dose.
Also embodiment of the present invention comprises the method for regulating the 5-HT function of receptors with formula (I) compound or the acceptable salt of its medicine of effective dose.
Another embodiment of the present invention provides the method for the treatment of or prevention central nervous system's disease, disease and/or situation.Described method comprises formula (I) compound or the acceptable salt of its medicine that gives described mammal treatment effective dose.
Formula (I) compound can be had activated disease specific, disease and/or a situation to it and be comprised obesity, depression, schizophrenia, anxiety neurosis, obsession, addiction, Panic disorder, sleep disorder, migraine, type ii diabetes, epilepsy, phobia and psychiatric syndrome.
Detailed Description Of The Invention
The present invention has used to give a definition, unless described otherwise:
Term used herein " alkyl " comprises and contains straight chain and the branched hydrocarbyl that specifies number carbon atom, the normally propyl group of methyl, ethyl and straight chain and side chain and butyl.Term " alkyl " also comprises cycloalkyl, i.e. ring-type C
3-C
8Alkyl is as cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.The separate base of indication or part, for example " propyl group " includes only straight chain group or part.Branched chain isomer is specifically indicated as " isopropyl ".
Term used herein " thiazolinyl " separately or contain replacement or unsubstituted straight-chain alkenyl or replacement or the unsubstituted branched-chain alkenyl of 2-10 carbon atom at the combination middle finger.The example of this group includes but not limited to vinyl, E-and Z-pentenyl, decene base etc.
Term used herein " alkoxyl " is independent or making up middle finger alkyl ether groups, wherein the same definition of term " alkyl ".The example of suitable alkyl ether groups includes but not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.
Term " halo " is defined as in this article and comprises fluorine, chlorine, bromine or iodine.Similarly, term " halogen " is defined as in this article and comprises fluorine, chlorine, bromine and iodine.
Term " amino " separately or comprise-NH in combination
2Or-NR
aR
bGroup, wherein R
aAnd R
bHydrogen, alkyl, alkylaryl or aryl independently.
Term " aryl " in this article separately or be defined as monocycle or bicyclic aromatic group (for example phenyl or naphthyl) in combination, it can not be substituted, perhaps by for example one or more, particularly one to three be selected from following substituent group and replace: H, halogen, CN, NO
2, CF
3, N
3, C
1-6Alkyl, OH, NR
aR
b, OC
1-6Alkyl, OR
a, C (=O) NR
aR
b, C (=S) NR
aR
b, tetrazole radical (tetrazoyl), triazolyl (triazoyl), amidino groups, guanidine radicals, sulfo-guanidine radicals, cyano group guanidine radicals and aryl.In general, " aryl " expression phenyl or have nine to ten annular atomses, wherein at least one ring is the ortho-fused bicyclic carbocyclic group (as naphthyl or tetralyl) of aromatic ring.Term " aryl " also is abbreviated as " Ar " in various chemical constitutions.
Term " heteroaryl " is defined as monocycle, dicyclo or the three-loop system that contains, two or three aromatic rings and contain at least one nitrogen, oxygen or sulphur atom in aromatic ring in this article; it can not be substituted, perhaps by for example one or more, particularly one to three following substituent group replacement: halogen, alkyl, hydroxyl, hydroxy alkyl, alkoxyl, alkoxyalkyl, haloalkyl, nitro, amino, alkyl amino, acyl amino, alkylthio group, alkyl sulphonyl and alkyl sulphonyl.the example of heteroaryl includes but not limited to the 2H-pyrrole radicals, the 3H-indyl, the 4H-quinolizinyl, the 4nH-carbazyl, acridinyl, benzo [b] thienyl, benzothiazolyl, the 13-carbolinyl, carbazyl, benzopyranyl, cinnolines base (cinnaolinyl), dibenzo [b, d] furyl, the furazan base, furyl, imidazole radicals, imidizolyl, indazolyl, indolizine base (indolisinyl), indyl, isobenzofuran-base, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, the naphthopyridine base, naphtho-[2,3-b], oxazolyl, pyrimidine radicals (perimidinyl), phenanthridinyl, the phenanthroline base, the phenarsazine base, phenazinyl, phenothiazinyl, folder oxygen thiaxanthene (phenoxathiinyl), phenoxazine group, the 2,3-benzodiazine base, pteridyl, purine radicals, pyranose, pyrazinyl, pyrazolyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrimidine radicals, pyrrole radicals, quinazolyl, quinolyl, quinoxalinyl, thiadiazolyl group, thianthrene group, thiazolyl, thienyl, triazolyl and xanthyl.In one embodiment, term " heteroaryl " expression contains five or six annular atomses, comprises carbon and 1,2,3 or 4 heteroatomic monocyclic aromatic rings, and described hetero atom independently is selected from non-peroxidating oxygen, sulfur and N (Z), and wherein Z does not exist or is H, O, C
1-4Alkyl, phenyl or benzyl.In another embodiment, heteroaryl represent its derivative approximately eight to the ortho-fused bicyclic heterocycle, particularly benzo derivative of ten annular atomses or by condensing the derivative derivant of propylidene or tetramethylene double-basis.
Term " Het " general proxy is saturated or fractional saturation, contain at least one hetero atom that is selected from oxygen, nitrogen and sulfur, optional by C
1-6Alkyl or C (=O) OR
6The heterocyclic radical that replaces.Usually, " Het " contains one or more heteroatomic monocycle, dicyclo or three cyclic groups that are selected from oxygen, nitrogen and sulfur." Het " group also can contain the oxygen base that is connected on ring (=O).The limiting examples of Het group comprises 1,3-Dihydrobenzofuranes, 1,3-dioxolane, 1,4-dioxane, Isosorbide-5-Nitrae-dithiane, 2H-pyrans, 2-pyrazoline, 4H-pyrans, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochroman base, iso-dihydro-indole-group, morpholine, piperazinyl, piperidines, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrrolin, quinuclidine and thiomorpholine.
The preferred embodiments of the invention comprise:
Embodiment 1:
R wherein
1And R
2Independently be selected from H, halogen, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, C
1-8Thiazolinyl, perhaloalkyl radical, CN, OR
5, SR
5, N (R
5)
2, CON (R
5)
2, NR
5COR
5, NR
5CO
2R
5, SO
2N(R
5)
2, NR
5SO
2R
5, aryl and heteroaryl, wherein said aryl or heteroaryl can be chosen wantonly by maximum three substituent groups that are selected from alkyl, halogen and alkoxyl and replace, perhaps R
1And R
2Form together 5 yuan or 6 rings;
R
3Be selected from H, C
1-8Alkyl, OR
5,-CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
3aH, perhaps R
3And R
3aBe together-CH
2CH
2-, perhaps R
2And R
3Form 5 yuan or 6 rings;
R
4Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5,-CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
4aH, perhaps R
3And R
3aBe together-CH
2CH
2-;
R
5Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, heteroaryl and perhaloalkyl radical, perhaps R
5Form hetero-aromatic ring together with atom that it connects.
Embodiment 2:
R wherein
1And R
2Independently be selected from H, halogen, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, C
1-8Thiazolinyl, perhaloalkyl radical, CN, OR
5, SR
5, N (R
5)
2, CON (R
5)
2, NR
5COR
5, NR
5CO
2R
5, SO
2N(R
5)
2, NR
5SO
2R
5, aryl and heteroaryl, wherein said aryl or heteroaryl can be chosen wantonly by maximum three substituent groups that are selected from alkyl, halogen and alkoxyl and replace, perhaps R
1And R
2Form together 5 yuan or 6 rings;
R
3Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5,-CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
3aH, perhaps R
3And R
3aBe together-CH
2CH
2-, perhaps R
2And R
3Form 5 yuan or 6 rings;
R
4Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5,-CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
4aH, perhaps R
3And R
3aBe together-CH
2CH
2-R
5Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, aryl, C
1-8Miscellaneous alkyl aryl, heteroaryl and perhaloalkyl radical, perhaps R
5Form hetero-aromatic ring together with atom that it connects.
Embodiment 3:
R wherein
1And R
2Independently be selected from H, halogen, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, C
1-8Thiazolinyl, perhaloalkyl radical, CN, OR
5, SR
5, N (R
5)
2, CON (R
5)
2, NR
5COR
5, NR
5CO
2R
5, SO
2N(R
5)
2, NR
5SO
2R
5, aryl and heteroaryl, wherein said aryl or heteroaryl can be chosen wantonly by maximum three substituent groups that are selected from alkyl, halogen and alkoxyl and replace, perhaps R
1And R
2Form together 5 yuan or 6 rings;
R
3Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5,-CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
3aH, perhaps R
3And R
3aBe together-CH
2CH
2-, perhaps R
2And R
3Form 5 yuan or 6 rings;
R
4Be selected from H, C
1-8Alkyl, C
1-8Alkylaryl, C
1-8Miscellaneous alkyl aryl, OR
5,-CH
2-O-C
1-8Alkyl ,-CH
2OH ,-COO-C
1-8Alkyl ,-CON (R
5)
2And aryl;
R
4aH, perhaps R
3And R
3aBe together-CH
2CH
2-;
R
5Be selected from H, C
1-8Alkyl, C
1-8Miscellaneous alkyl aryl, C
1-8Alkylaryl, aryl, heteroaryl and perhaloalkyl radical, perhaps R
5Form hetero-aromatic ring together with atom that it connects.
Preferred X is S;
R
1Be selected from halogen, C
1-8Alkyl, OR
5, SO
2N(R
5)
2And perhaloalkyl radical;
R
2Be selected from hydrogen, halogen, C
1-8Alkyl and OR
5, perhaps with R
3Form together 5 rings;
R
3Hydrogen or C
1-8Alkyl;
R
3Hydrogen;
R
4Hydrogen or C
1-8Alkyl;
R
4Hydrogen;
R
5Hydrogen or C
1-8Alkyl perhaps forms hetero-aromatic ring together with atom that it connects.
At present preferred compound comprises:
1) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2) the 2-bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
3) the 2-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
4) 2,3-two bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
5) 2,3-two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
6) 2-bromo-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
7) (R, S) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-4-alcohol;
8) 2-chloro-4-methoxy-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
9) 2-chloro-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
10) 2,3-dichloro-4,4-methyl-5,6,7,8-tetrahydrochysene-thieno [2,3-d] azepine;
11) 2-(4-Trifluoromethoxyphen-l)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
12) 2-(3-trifluoromethyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
13) 2-(2-trifluoromethyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
14) 2-(4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
15) 2-(2,5-difluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
16) 2-(3-chloro-4-fluorobenzene A Ji)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
17) 2-(2,5-Dichlorobenzene base)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
18) 2-(5-fluorine 2-methoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
19) 2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
20) 2-(4-ethoxyl phenenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
21) 2-(4-ethylphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
22) 2-(3-methoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
23) 2-phenyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
24) 2-(3-fluorine biphenyl-4-yl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
25) 2-(2-fluorine biphenyl-4-yl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
26) 2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
27) 2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
28) 2-bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
29) 2-bromo-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
30) 2-(pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
31) N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
32) N, N-dimethyl-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
33) the 2-bromo-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
34) 2-methyl-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
35) trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
36) 3-bromo-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
37) the 2-tert-butyl group-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
38) 2-naphthalene-1-base-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
39) 2-naphthalene-2-base-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
40) 2-(2,6-difluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
41) 3-(2,6-difluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
42) 2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
43) 3-bromo-2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
44) 2-amino-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-3-Ethyl formate;
45) 2-amino-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-c] azepine-3-Ethyl formate;
46) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-3-Ethyl formate;
47) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-c] azepine-3-Ethyl formate.
Particularly preferred compound comprises:
1) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2) 2,3-two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
3) 2-bromo-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
4) 2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
5) 2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
6) 2-bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
7) 2-bromo-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
8) 2-(pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
9) N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
10) N, N-dimethyl-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
11) the 2-bromo-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
12) 2-methyl-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
13) trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
14) 3-bromo-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine; With
15) the 2-tert-butyl group-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine.
Some compound of the present invention can exist with different isomer (for example enantiomer and diastereomer) form.The present invention has imagined purified form and the mixed form of all this isomers, comprises racemic mixture.In the enol form is also included within.
Compound of the present invention can exist with the form of non-solvent compound and solvate, comprises hydrated form, for example semihydrate.In general, for purpose of the present invention, suitable with non-solvent compound form with the solvate form thereof of the acceptable solvent of medicine such as water, ethanol etc.
Some compound of the present invention also can form the acceptable salt of medicine, for example acid-addition salts.For example, nitrogen-atoms can with sour salify.The example that is used for the appropriate acid of salify comprises hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, ascorbic acid, maleic acid, methanesulfonic acid and well known to a person skilled in the art other mineral acids and carboxylic acid.These salt are to prepare by free alkali form being contacted with the required acid of capacity produce salt.Process the salt of gained with suitable dilute alkaline aqueous solution such as rare potassium hydroxide aqueous solution, wet chemical, weak ammonia and dilute aqueous solution of sodium bicarbonate, can make free alkali form regeneration.Each free alkali form and their salt forms separately are upper slightly different in some physical property (as the dissolubility in polar solvent), but for the object of the invention, each acid salt is suitable with their free alkali forms separately.(referring to such as S.M.Berge etc., " Pharmaceutical Salts, " J.Pharm.Sci, 66:1-19 (1977), the document is incorporated herein by reference.
Term used herein " compositions " means to comprise the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.
Compound of the present invention can use with the form derived from mineral acid or organic acid drug acceptable salt.Word " the acceptable salt of medicine " refers to be suitable for contacting with zootic tissue and excessive toxicity, stimulation, anaphylaxis etc. not occurring with the mankind in reliable medical judgment scope, and with rational effect/risk than the salt that matches.The acceptable salt of medicine is well known in the art.For example, S.M.Berge etc. exists
J.Pharmaceutical Sciences, in 1977,66:1 (under reaching), the acceptable salt of medicine is described in detail.Described salt can be by making the compounds of this invention the free alkali degree of functionality and suitable organic acid reaction, in final separation and the preparation of purge process situ or the preparation separately of the compounds of this invention.representational acid-addition salts includes but not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, caproate, fumarate, hydrochlorate, hydrobromate, hydriodate, different thiosulfate (isothionate), lactate, maleate, mesylate, nicotinate, the 2-naphthalene sulfonate, oxalates, palmitate, pectate, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, tartrate, rhodanate, phosphate, glutamate, Glu, bicarbonate, tosilate and hendecane hydrochlorate.Equally, alkaline nitrogen-containing group can be quaternized with following material: elementary alkyl halide such as methyl, ethyl, propyl group and butyl chloride, bromine and iodine; Sulphuric acid dialkyl such as dimethyl sulfate, diethylester, dibutyl ester and diamyl ester; Long-chain halogenide such as decyl, dodecyl, myristyl and octadecyl chloride, bromine and iodine; Aryl alkyl halogen such as benzyl bromide a-bromotoluene and phenethyl bromide and other aryl alkyl halogen.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to form the acceptable acid-addition salts of medicine comprises mineral acid example hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, organic acid such as oxalic acid, maleic acid, succinic acid and citric acid.
Base addition salts can contain carboxylic moiety and suitable alkali reaction by what make the compounds of this invention, final separation and the preparation of purge process situ at the compounds of this invention, the hydroxide of alkali such as the acceptable metal cation of medicine, carbonate and bicarbonate, perhaps ammonia or organic primary amine, secondary amine or tertiary amine.The acceptable salt of medicine includes but not limited to based on the cation of alkali metal or alkaline-earth metal such as lithium, sodium, potassium, calcium, magnesium and aluminum salt etc., and nontoxic quaternary ammonium and amine cation, comprise ammonium, tetramethyl-ammonium, tetraethyl ammonium, ammonium methyl, Dimethyl Ammonium, trimethyl ammonium, triethyl ammonium, diethyl ammonium and ethyl ammonium etc.Other representative organic amines that can be used for forming base addition salts comprise ethylenediamine, ethanolamine, diethanolamine, piperidines, piperazine etc.
Comprise powder, spray, ointment and inhalant for the local dosage form that gives the compounds of this invention.Under aseptic condition with reactive compound and medicine acceptable carrier and any required antiseptic, buffer agent or propellants.Ophthalmic preparation, eye ointment, powder and solution also are conceived within the scope of the present invention.
The reactive compound amount of gained can change the actual dose level of each active component in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, compositions and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the order of severity of the disease for the treatment of and the patient's to be treated state of an illness and the medical history of particular compound.But the way of this area is, the dosage of compound is from lower than increasing gradually dosage, until obtain required effect for obtaining level that required therapeutic effect requires.
When being used for above-mentioned treatment or other treatment, a kind of the compounds of this invention for the treatment of effective dose can be used with pure form, perhaps uses with the acceptable salt of medicine, ester or prodrug forms (in the situation that having these forms).Perhaps, described compound can be accepted the pharmaceutical composition administration of excipient to contain this purpose compound and one or more medicines.The compounds of this invention of word " treatment effective dose " refers to be applicable to the reasonable effect/risk of any therapeutic treatment than the compound of sanatory q.s.But the total consumption per day that it should be understood that the compounds of this invention and compositions must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root for the treatment of effective dose is decided according to many factors, comprises the order of severity of the disease for the treatment of and this disease; The activity of the particular compound that adopts; The concrete compositions that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; The treatment persistent period; The medicine that is used in combination with the particular compound that adopts or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than increasing gradually dosage, until obtain required effect for obtaining level that required therapeutic effect requires.
Giving people or the total daily dose of zootic the compounds of this invention can be approximately 0.0001 to the scope of approximately 1000mg/kg/ days.For the purpose of oral administration, more preferably dosage can be approximately 0.001 to the about scope of 5mg/kg/ days.If necessary, effectively daily dose can be divided into multiple dose for the administration purpose; Therefore, unit-dose composition can contain this quantity or its divided dose, to consist of daily dose.
The present invention also provides the pharmaceutical composition that comprises with one or more nontoxic drug acceptable carriers the compounds of this invention formulated together.That described pharmaceutical composition can be mixed with especially specially is for oral administration with solid or liquid form, for the parenteral injection or for rectally.
Pharmaceutical composition of the present invention can by in oral, rectum, parenteral, pond, intravaginal, intraperitoneal, part (as by powder, ointment or drop), a mouthful cheek give the mankind and other mammals, perhaps give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenous, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
In yet another aspect, the invention provides and comprise the pharmaceutical composition that composition of the present invention and physiology can tolerate diluent.The present invention includes one or more above-claimed cpds, its can tolerate with one or more nontoxic physiology or acceptable diluent, carrier, adjuvant or vehicle (this paper is referred to as diluent with them) together be mixed with compositions, for parenteral injection, intranasal transmission, with solid or liquid form oral administration, rectum or topical etc.
The present composition also can by at target site through the conduit localized delivery, by intracoronary stent (tube that is formed by fine and closely woven metal gauze) or transmit by biodegradable polymer.The compounds of this invention also can be compound with part such as antibody, for the orientation transmission.
The compositions that is suitable for the parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersant, suspensoid or Emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersant.Suitable moisture or nonaqueous carrier, diluent, solvent or vectorial example comprise water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), vegetable oil (as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositionss also can contain adjuvant, as antiseptic, wetting agent, emulsifying agent and dispersant.By various antibacterial agents and antifungal, such as parabens, chlorobutanol, phenol, sorbic acid etc. can guarantee to prevent the effect of microorganism.Also should comprise isotonic agent, such as saccharide, sodium chloride etc.By using the material postpone absorption, for example aluminum monostearate and gelatin, the prolongation absorption that can reach the injectable drug form.
Also can contain suspending agent except the active ingredient beyond the region of objective existence in suspensoid, such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, bentonite, agar and Tragacanth or these materials partially.
In some cases, be the effect of prolong drug, the absorption subcutaneous or the intramuscular injection medicine of should slowing down.This can be by realizing with the crystal of poorly water-soluble or the liquid suspension of amorphous substance.Like this, the infiltration rate of medicine is decided by its dissolution velocity, and dissolution velocity can be decided by crystal size and crystal formation.Perhaps, the delay of the medicament forms of parenteral absorb by with this medicine dissolution in or be suspended in oily vehicle and realize.
The injectable depot formulations form can prepare by the microcapsule substrate that forms medicine in biodegradable polymer such as polylactide-PGA.Can according to the character of medicine with ratio with the concrete polymer that adopts of polymer, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe and polyanhydride.Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or microemulsion in prepare.
Injectable formulation can be for example by filtering or sterilize by the biocide that mixes the aseptic solid composite form with bacteria filter, and described solid composite can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
Solid dosage forms for oral administration comprises capsule, tablet, pill, powder and granule.In this solid dosage forms, reactive compound can be accepted excipient or carrier such as sodium citrate or dicalcium phosphate and/or following material with the medicine of at least a inertia and mix: a) filler or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) binding agent such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis; C) wetting agent such as glycerol; D) disintegrating agent such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate; E) solution blocker such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as spermol and glyceryl monostearate; H) adsorbent such as Kaolin and bentonite and i) lubricant such as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.In the situation that capsule, tablet and pill also can comprise buffer agent in dosage form.
The solid composite of similar type uses such as lactose and high molecular weight polyethylene glycol etc. of excipient, also can be used as the implant in soft capsule and hard capsule.
The solid dosage forms of tablet, dragee, capsule, pill and granule can prepare together with coating and shell material such as enteric coating and known other coatings of field of medicine preparations.These solid dosage formss can be chosen wantonly and contain opacifier, and its composition also can make it just or preferentially choose wantonly with the delayed mode release of active ingredients at certain position of intestinal.The example of operable embedding composition comprises polymer substance and wax.
As suitable, reactive compound also can be made into the microcapsule form with one or more above-mentioned excipient.
Liquid dosage form for oral administration comprises the acceptable Emulsion of medicine, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent such as water or other solvents commonly used except containing the active ingredient beyond the region of objective existence, solubilizing agent and emulsifying agent such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol and the fatty acid ester of sorbitan and their mixture.
Orally administered composition also can comprise adjuvant except comprising inert diluent, as wetting agent, emulsification suspending agent, sweeting agent, correctives and flavouring agent.
The compositions of confession rectum or vagina administration is suppository preferably.Suppository can be by mixing the compounds of this invention and suitable non-irritating excipient or carrier such as cocoa butter, Polyethylene Glycol or suppository wax to prepare, it is at room temperature solid, therefore but next at body temperature is liquid, can melt in rectal cavity or vaginal canal and discharges reactive compound.
The compounds of this invention also can the liposome form administration.As known in the art, liposome makes with phospholipid or other lipid materials usually.Liposome is formed by the single or multiple lift aquation liquid crystal that is scattered in water-bearing media.Can accept on any nontoxic, physiology that can form liposome and metabolizable lipid all can use.The present composition of liposome form also can contain stabilizing agent, antiseptic, excipient etc. except containing the compounds of this invention.Preferred lipid is natural and synthetic phospholipid and phosphatidylcholine (lecithin), and they can use separately or together.
The method that forms liposome is well known in the art.Referring to for example Prescott (editor),
Methods in Cell Biology.XIV roll up, Academic Press, New York, N.Y. (1976), p.33 (and under).
Term used herein " medicine can be accepted prodrug " represents the prodrug of the compounds of this invention, it is suitable for contacting with zootic tissue with the mankind in reliable medical judgment scope and excessive toxicity, stimulation, anaphylaxis etc. do not occur, match with rational effect/risk ratio and effective to its intended purpose, in the situation that the possible zwitterionic form that also represents the compounds of this invention.Prodrug of the present invention can be for example by hydrolysis in blood in vivo rapid conversion become the parent compound of following formula.T.Higuchi and V.Stella,
Pro-drugs as NovelDelivery Systems.A.C.S.Symposium Series the 14th volume and Edward B.Roche (editor),
Bioreversible Carriers in Drug Design, this being provided comprehensive discussion in American PharmaceuticalAssociation and Pergamon Press (1987), above-mentioned document is incorporated herein by reference.
The compounds of this invention can be by the method preparation that proposes in flow process hereinafter.All embodiment all adopt general analysis condition proposed below.
The general analysis condition:
HPLC analyzes and purification carries out with Waters 2525 binary gradient pumps, Waters 2767 sample managing devices, Waters 2487 UV monitors (220 and 254nM) and Waters Micromass ZQ Electrospray Mass Spectrometry monitor.Micromass ZQ has set positive and negative ionization mode (cone voltage equals respectively 25 and 50) simultaneously.Carry out analytical type HPLC by following condition:
Waters XTerra MS C18 50 * 4.6mm 3.5 μ m posts
Mobile phase: 10mM ammonium acetate buffer (pH 5.75) and acetonitrile
Acetonitrile: 10-75% (to 3.5 minutes), 75-99% (to 3.9 minutes), 99% kept 4.2 minutes, 99-10% (to 4.5 minutes), rebalancing.
Carry out analytical type HPLC by following condition:
Waters XTerra Prep MS C1 8 50 * 19mm 5 μ m posts
Mobile phase: 10mM ammonium acetate buffer (pH 5.75) and acetonitrile
Acetonitrile: 10-99% (to 8 minutes), 99% kept 9 minutes, 99-10% (to 9.5 minutes), rebalancing.
NMR analyzes and carries out with Bruker BioSpin UltraShield NMR (300MHz).
Flow process 1a: trifluoromethyl and a halogenated thiophene base azepine synthetic
Flow process 1b: dihalo and 3-bromo-2-trifluoromethyl thiophene base azepine synthetic
Flow process 2: biaryl thienyl azepine synthetic
Flow process 3: alkyl and benzyl thienyl azepine analog synthetic
Synthesizing of flow process 4.2-bromo-3 methyl thiophene base azepine and 2,3-dichloro-thiophene base azepine and related analogs
Synthesizing of flow process 5.3-methoxythiophene base azepine
Synthesizing of the 4-methylthiophene base azepine of flow process 6. halos and related compound
*Expression is separated to the material of enantiomer-pure
Synthesizing of the 8-methylthiophene base azepine of flow process 7. halos and related compound
*Expression is separated to the material of enantiomer-pure
Synthesizing of flow process 8.2-sulfonamido and 2-acylamino-thienyl azepine
Synthesizing of flow process 9:3-alkylthrophene base azepine and related analogs
*Expression is separated to the material of enantiomer-pure
Synthesizing of 10: three penthienate azepine derivatives of flow process
*Expression is separated to the material of enantiomer-pure
Flow process 11: furyl azepine synthetic
Embodiment 1.
2-bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1a)
a.)
[ethoxy carbonyl-(2-thiophene-2-base ethyl) amino] ethyl acetate:
2-thiophene-2-base ethamine (21g, 165mmol) is stirred in 1L DCM.Add glyoxylic acid ethyl ester (165mmol, 50% toluene solution), then add 50 μ L HOAc.Then stirring reaction 10 minutes slowly adds NaBH (OAc)
3(214mmol, 45g).Add HOAc (214mmol) after 15 minutes, stirring reaction 20 minutes.Reactant is concentrated, and thick material is dissolved in respectively respectively in the THF of 500mL and water.Add NaHCO
3(42g, 500mmol) then adds ethyl chloroformate (21mL, 214mmol).Slowly add saturated NaHCO in reactant
3, until air release reaches minimum.After reactant stirs and spends the night, with EtOAc (400mL) dilution.Product extraction (2x) in EtOAc, is used MgSO
4Drying, concentrated, obtain the subtitle product, be dark oil, it is used without being further purified namely.
B.) [ethoxy carbonyl-(2-thiophene-2-base ethyl)-amino]-acetic acid:
With step a) the thick material of gained (~165mmol) be dissolved in EtOH (700mL), process with the 1M NaOH of 600mL.Reactant is acidified to pH~1 with dense HCl after stirring and spending the night.The crude reaction thing with EtOAc (400mL) dilution, is washed with water.Water is stripped with EtOAc.With organic extract water (2x) washing that merges, use MgSO
4Dry.Concentrated and evaporation, obtain the subtitle product from toluene (2x), is solid, and it is used without being further purified namely.
C.) 4-oxo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step b) product (~165mmol) be dissolved in IL DCM.Add DMF (100 μ L), then slowly add oxalyl chloride (21.7mL, 247mmol).After 1 hour, reactant is concentrated into dried, thick material is dissolved in DCE (IL) again.Carefully add ACl
3(55g, 410mmol), at room temperature stirring reaction is 1/2 hour.The crude reaction thing with the ice quencher, is diluted with EtOH (300mL), and MgSO is used in water (3x) washing
4Dry.Title product obtains the 10.5g subtitle compounds by silica gel column chromatography (30%EtOAc/ hexane) purification, is pale solid.MS:ESI (cation): 240 (M+H).
D.) 4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With AlCl
3(3.95g, 29.7mmol) joins in the 50mL DCM of 0 ℃.Add borine-tert-butylamine complex (5.2g, 59.5mmol), then add the step c that is dissolved in DCM (50mL)) product (2.37g, 9.9mmol).At room temperature stirring reaction is 2 hours, and then adds 3.95g (29.7mmol) AlCl
3After stirring reaction 10 minutes, with 0.1M HCl (~50mL) careful quencher.After concentrated organic solvent, crude product mixture is distributed between 1M HCl and EtOAc (each 70mL).With water layer with EtOAc strip (1x).The organic layer MgSO that merges
4Drying, concentrated.By obtaining subtitle product (1.45g) after silica gel column chromatography (EtOAc/ hexane gradient) purification.
1H NMR (300MHz, CDCl
3) 6.96 (d, J=5Hz, 1H), 6.76 (d, J=5Hz, 1H), (4.18 q, J=7Hz, 2H), 3.52-3.78 (m, 4H), (2.78-3.08 m, 4H), 1.28 (t, J=7Hz, 3H) .MS:ESI (cation): 226 (M+H).
E.) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With steps d) product (200mg, 0.89mmol) is dissolved in 15mL CHCl
3In, process with TMSI (4.5mmol, 600 μ L).Be heated to 70 ℃ spend the night after, carefully will react quencher with MeOH (10mL) and 1MNaOH (20mL).Subtitle compounds is extracted into DCM (in 3 * 20mL).Extract MgSO
4Drying, concentrated, obtain the 178mg subtitle compounds.
1H NMR (300MHz, DMSO) 7.20 (d, J=5Hz, 1H), 6.85 (d, J=5Hz, 1H), 3.42-3.61 (m, 4H), 2.71-3.03 (M, 4H) .MS:ESI (cation): 154 (M+H).
F.) 4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
To be dissolved in 50: 50 acetone/water mixture (8mL) step e) product (296mg, 1.93mmol) is with the NaHCO of 0 ℃
3(340.5mg, 4.03mmol) processes, and stirs 30 minutes.Add Bis(tert-butoxycarbonyl)oxide (463mg, 2.12mmol) in the solution of gained.Reactant mixture was stirred 14 hours at ambient temperature.Reactant mixture is poured in water (50ml), with EtOAc (3 * 50ml) extractions.The organic facies that merges is washed with saline (75ml), dry (MgSO
4), vacuum concentration obtains crude product, is oil.Obtain subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification, be limpid oil; Productive rate (93%).
1H NMR (300MHz, CDCl
3) δ 6.96 (d, J=5Hz, 1H), 6.76 (d, J=5Hz, 1H), 3.44-3.68 (m, 4H), 2.76-3.06 (m, 4H), 1.50 (s, 9H) .MS:ESI (cation): 254 (M+H).
G.) the 2-bromo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
To be dissolved in 50: 50 chloroform/acetate mixture (1ml) step f) product (10mg, 0.039mmol) processes with N-bromosuccinimide (7mg, 0.041mmol).Stirred reaction mixture is 30 minutes at ambient temperature.Reactant mixture is poured in water (5ml), used CHCl
3(3 * 5ml) extractions.The organic facies that merges is washed with 10%KOH solution (5ml), saline (5ml), dry (MgSO
4), concentrated, obtain crude product, be oil.Obtain subtitle compounds by the HPLC purification, be oil.
MS:ESI (cation): 332,334 (M+H).
H.) the 2-bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
To be dissolved in the step g of ether (1ml)) product (0.39mmol) 4M HCl/ dioxane (1ml) processing.Stirred reaction mixture is 18 hours at ambient temperature.Filter the precipitate of gained, with the anhydrous diethyl ether washing, obtain the HCl salt of title compound.
1H NMR (300MHz, DMSO) δ 9.40 (s, 2H), 7.05 (s, 1H), 3.14-3.33 (m, 4H), 2.94-3.23 (m, 2H), 2.76-3.06 (m, 2H) .MS:ESI (cation): 232,234 (M+H).
Embodiment 2.
2-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1a)
A.) the 2-chloro-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
To be dissolved in CHCl
3(1ml) and the embodiment 1 step f of HOAc (1mL)) product (embodiment 1 for 10mg, 0.039mmol) processes with N-chlorosuccinimide (6mg, 0.041mmol).Stirred reaction mixture is 12 hours at ambient temperature.Reactant mixture is poured in water (5ml), used CHCl
3(3 * 5ml) extractions.The organic facies that merges is washed with 10%KOH solution (5ml), saline (5ml), dry (MgSO
4), concentrated, obtain crude product, be oil.Obtain subtitle compounds by the HPLC purification, be limpid oil.MS:ESI (cation): 288 (M+H).
B.) the 2-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.
1H NMR (300MHz, DMSO) δ 6.72 (s, 2H), 2.78-2.85 (m, 2H), 2.72-2.79 (m, 4H), 2.51-2.70 (m, 2H) .MS:ESI (cation): 188 (M+H).
Embodiment 3.
2,3-, two bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1b)
A.) 2,3-two bromo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 1 steps d) product (95mg, 0.42mmol) is dissolved in CHCl
3(1ml) and in HOAc (1mL), process with NBS (66.7mg, 0.42mmol).Stirred reaction mixture is 20 minutes at ambient temperature.Add sodium acetate (138mg, 1.68mmol) and extra NBS (133.4mg, 0.84mmol) in this mixture.At 60 ℃ of lower stirred reaction mixtures, complete reaction until measure through LC/MS.Reactant mixture is cooled to ambient temperature, with saturated sodium bicarbonate (2ml) dilution, uses CHCl
3(3 * 2ml) extractions.The organic facies that merges is washed with saline (10ml), dry (MgSO
4), vacuum concentration obtains product, is thick oil.Obtain subtitle compounds by flash chromatography (EtOAc/ hexane gradient) purification, be oil.MS:ESI (cation): 384 (M+H).
B.) 2,3-two bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step b) product (0.42mmol) is dissolved in DCM (2ml), processes with iodo three monosilanes (0.46mmol).With reactant mixture stirring and refluxing 24 hours.Reactant mixture is poured in saturated sodium bicarbonate (10ml), with dichloromethane (3 * 5ml) extractions.The organic facies that merges is washed with saline (10ml), dry (MgSO
4), vacuum concentration obtains oil.Obtain title compound through the preparation HPLC purification.
1H NMR (300MHz, CDCl
3) δ 2.94-3.05 (m, 4H), 2.85-2.92 (m, 4H), 1.92 (s, 1H) .MS:ESI (cation): 312 (M+H).
Embodiment 4.
2,3-, two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 4)
A.) (4,5-dichloro-thiophene-2-yl)-oxo-acetic acids ethyl ester:
Under 5-10 ℃, chloro-oxo-acetic acids ethyl ester (5.43ml, 48.7mmol) is joined in 2,3-dichloro-thiophene (5g, 32.6mmol).Slowly drip AlCl
3The Nitrocarbol. solution (13ml) of (6.49g, 48.7mmol) makes internal reaction temperature not be increased to more than 10 ℃.After 1 hour, reactant mixture is poured in frozen water, used CH
2Cl
2(2 * 100ml) extractions.Organic layer 10%NaHCO
3(2 * 50ml), water (1 * 50ml) and saline (1 * 50ml) washing.Dry (Na
2SO
4), concentrated, obtain the light orange solid, obtain 6.8g (82%) subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification.
B.) (4,5-dichloro-thiophene-2-yl)-hydroxyl-ethyl acetate:
With step a) THF of product (23.0g, 90.9mmol) (500ml) solution with NaBH (OAc)
3(23.1g, 109mmol) and AcOH (250 μ l) processed 1 hour under 60 ℃.To react the quencher with AcOH (8ml), be concentrated into~250ml.With reactant H
2CH is used in O (400ml) dilution
2Cl
2(1 * 400ml; 1 * 100ml) extraction.With the dry (MgSO of organic layer
4), concentrated, obtain the 23g subtitle compounds.
1H?NMR(300MHz,CDCl
3)δ6.91(s,1H);5.25(dd,J
1=6Hz,J
2=1Hz,1H);4.22-4.40(m,2H);3.52-3.60(br?m,1H);1.33(t,J=7Hz,3H).
C.) (4,5-, two chloro-3-methoxycarbonyl methylthiophene-2-yls)-ethyl acetate:
With step b) naphthalane (145ml) solution of product (12.2g, 48.0mmol) is with trimethyl orthoacetate (24.5ml, 192mmol) and caproic acid (0.61ml) processing.Flask is equipped with Vigreux column, and is heated to 180 ℃.Regularly added extra caproic acid (3ml) in 6 hours, reacting by heating is spent the night.Reactant is concentrated on rotavap, and residue extracts with MeOH (100ml * 2).The MeOH extract is concentrated, by silica gel column chromatography (EtOAc/ hexane gradient) purification, obtain 4.36g (29%) subtitle compounds.MS:ESI (cation): 311,313 (M+H).
D.) (3-carboxymethyl-4,5-dichloro-thiophene-2-yl) acetic acid:
Under 0 ℃ with step c) MeOH (7ml) solution of product (1.14g, 3.66mmol) processes by dripping 2M NaOH (3.8ml).Reactant is warming up to 22 ℃, and stirring is spent the night.Evaporating solvent is dissolved in residue in 2M NaOH (50ml), with ether (2 * 50ml) extractions.Alkaline layer is cooled to 0 ℃, is acidified to pH 1 with 6M HCl.(4 * 100ml) strip, with the dry (MgSO of organic layer with EtOAc with acidic layer
4), concentrated.Thick solid is ground with hexane, filter, obtain the subtitle compounds of 2.75g (73%).
MS:ESI (anion): 267,269 (M-H).
E.) 2-[4,5-two chloro-3-(2-ethoxy)-thiophene-2-yl] ethanol:
With steps d) THF (85ml) solution of product (2.5g, 9.33mmol) is cooled to 0 ℃, drips 1M BH in 10 minutes
3-THF (46.6ml, 46.6mmol) solution stirred after dropwising 20 minutes again.Reactant is warming up to 22 ℃, stirred 2 hours.Pour reactant into ice-cold saturated NaHCO
3(150ml), extract with EtOAc.Make crude product pass through silica gel plug, wash with EtOAc.Concentrate eluant obtains the subtitle compounds of 1.99g (88%).
F.) methanesulfonic acid 2-[4,5-two chloro-2-(2-mesyloxy ethyl)-thiene-3-yl-] ethyl ester:
With step e) CH of product (1.99g, 8.25mmol)
2Cl
2(41ml) solution is cooled to 0 ℃, processes with triethylamine (3.4ml, 24.7mmol), then drips mesyl chloride (1.4ml, 18.1mmol) in 10 minutes.After 45 minutes, with crude reaction thing CH
2Cl
2(100ml) dilution, with frozen water (25ml), 10% citric acid (2 * 25ml), saturated NaHCO
3(2 * 25ml) and saline (1 * 25ml) washing.With the dry (mgSO of organic layer
4), be concentrated into 20ml, dilute with anhydrous dioxane (76ml).This mixture is concentrated, remove remaining CH
2Cl
2, the dioxane solution of gained changes next reaction over to.
G.) 6-benzyl-2,3-two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step f) the dioxane dimethanesulfonate solution that produces transfers in the 3 neck reaction flasks that Dropping funnel and condenser are housed.Add Anhydrous potassium carbonate (4.93g, 35.7mmol), content is heated to reflux.Then, drip anhydrous dioxane (27ml) solution of benzylamine (2.71g, 25.3mmol) in 45 minutes, continue heating 16 hours.Salt is leached concentrated solvent.Crude product obtains the subtitle compounds of 1.43g (62%) by silica gel column chromatography (EtOAc/ hexane gradient) purification.
1H NMR (300MHz, CDCl
3) δ 7.20-7.40 (m, 5H); (3.73 s, 2H); (2.68-2.89 m, 8H); MS:ESI (cation): 312,314 (M+H).
H.) 2,3-two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine hydrochlorate:
With step g) anhydrous dichloroethanes (11.6ml) solution of product (727mg, 2.33mmol) is cooled to 0 ℃, processes with chloro-carbonic acid 1-chloroethene ester (1.27ml, 11.65mmol), and reactant is warming up to 22 ℃ kept 1 hour.With reactant CH
2Cl
2(50ml) dilution, use saturated NaHCO
3(25ml) washing.With saturated NaHCO
3Use CH
2Cl
2Strip, the organic layer of merging washs with saline (25ml), dry (MgSO
4), concentrated, obtain the oily residue, absorb and refluxed 1 hour with anhydrous MeOH (75ml).Evaporation MeOH, thick residue grinds with ether, filters, and obtains the subtitle compounds of 323mg (54%).
1H NMR (300MHzDMSO) δ 9.60 (br s, 2H); (3.14-3.28 m, 6H); (2.97-3.50 m, 2H); MS:ESI (cation): 222,224 (M+H).
Embodiment 5.
2-bromo-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1b)
A.) 2-bromo-3-chloro-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
With embodiment 1 step f) product (54mg, 0.21mmol) is dissolved in CHCl
3(1ml) and in HOAc (1mL), with hydroquinone (2mg, 0.02mmol) and N-bromosuccinimide (38mg, 0.21mmol) processing.After stirring at ambient temperature 20 minutes, add N-chlorosuccinimide (28mg, 0.21mmol), continue to stir at ambient temperature 48 hours.Reactant mixture is poured in saturated sodium bicarbonate (10ml), with chloroform (3 * 5ml) extractions.The organic facies that merges is washed dry (MgSO with saline (10ml)
4), concentrated, obtain thick oil, it is used without being further purified namely.
B.) 2-bromo-3-chloro-5.6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine hydrochlorate:
Use a) product of step, by embodiment 1 step h) method prepare title compound.
1H NMR (300MHz, DMSO) δ 9.12 (bs, 2H); (3.22-3.31 m, 4H); (3.13-3.20 m, 2H); (2.98-3.05 m, 2H) .MS:ESI (cation): 266,268 (M+H).
Embodiment 6.
2-(4-Trifluoromethoxyphen-l)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A) 2-(4-Trifluoromethoxyphen-l)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
With embodiment 1 step g) product (20mg, 0.06mmol) is dissolved in DME (5mL), with acid chloride (1mg, 0.004mmol), triphenylphosphine (4.7mg, 0.018mmol) and 1M sodium carbonate (Na
2CO
30.45mL) process.Mixture was stirred 5 minutes at ambient temperature, then use 4-Trifluoromethoxyphen-l boric acid (28.4mg, 0.138mmol) to process.After 5 hours, add extra 4-Trifluoromethoxyphen-l boric acid (6.2mg, 0.03mmol) in heating under 85 ℃, continue to stir 12 hours.Reactant mixture is cooled to ambient temperature, makes it pass through to do the celite pad, filter the silicon dioxide plug, with DCM (5ml) and EtOAc (5mL) eluting.Evaporation filtrate obtains subtitle compounds, is thick oil, and it is used without being further purified namely.
B.) 2-(4-Trifluoromethoxyphen-l)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.With the reactant mixture vacuum concentration, through the preparation HPLC purification, obtain title compound.
1H NMR (300MHz, DMSO) δ 7.76 (d, J=8Hz, 2H), 7.48 (d, J=8Hz, 2H), 7.36 (s, 1H), (2.77-3.06 m, 8H), 2.0 (s, 1H) .) .MS:ESI (cation): 314 (M+H).
Embodiment 7.
2-(2-trifluoromethyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-(2-trifluoromethyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
Use the 2-trifluoromethyl phenyl boronic acid, prepare subtitle compounds by embodiment 6 steps method a).
B.) 2-(2-trifluoromethyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.With the reactant mixture vacuum concentration, through the preparation HPLC purification, obtain title compound.MS:ESI (cation): 298 (M+H).
Embodiment 8.
2-(4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-(4-fluorophenyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
Use 4-fluorophenyl boric acid, prepare subtitle compounds by embodiment 6 steps method a).
B.) 2-(4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.With the reactant mixture vacuum concentration, through the preparation HPLC purification, obtain title compound.MS:ESI (cation): 248 (M+H).
Embodiment 9.
2-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-(3-chloro-4-fluorophenyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
Use 3-chloro-4-fluorophenyl boric acid, prepare subtitle compounds by embodiment 6 steps method a).
B.) 2-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.With the reactant mixture vacuum concentration, through the preparation HPLC purification, obtain title compound.MS:ESI (cation): 282 (M+H).
Embodiment 10.
2-(2,5-Dichlorobenzene base)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-(2,5-Dichlorobenzene base)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
Use 2,4-Dichlorobenzene base boric acid, by embodiment 6 steps a) method prepare subtitle compounds.
B.) 2-(2,5-Dichlorobenzene base)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.With the reactant mixture vacuum concentration, through the preparation HPLC purification, obtain title compound.MS:ESI (cation): 298 (M+H).
Embodiment 11.
2-(4-ethylphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-(4-ethylphenyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
Use 4-ethylphenyl boric acid, prepare subtitle compounds by embodiment 6 steps method a).
B.) 2-(4-ethylphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.What make an exception is with the reactant mixture vacuum concentration, through the preparation HPLC purification, obtains title compound.MS:ESI (cation): 258 (M+H).
Embodiment 12.
2-(3-methoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-(3-methoxyphenyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-t-butyl formate:
Use 3-methoxybenzene ylboronic acid, prepare subtitle compounds by embodiment 6 steps method a).
B.) 2-(3-methoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.What make an exception is with the reactant mixture vacuum concentration, through the preparation HPLC purification, obtains title compound.MS:ESI (cation): 260 (M+H).
Embodiment 13.
2-phenyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 2)
A.) 2-phenyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-6-t-butyl formate:
Use phenylboric acid, prepare subtitle compounds by embodiment 6 steps method a).
B.) 2-phenyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 1 step h) method prepare title compound.What make an exception is with the reactant mixture vacuum concentration, through the preparation HPLC purification, obtains title compound.MS:ESI (cation): 230 (M+H).
Embodiment 14.
2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 3)
A.) the 2-bromo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 1 steps d) product (300mg, 1.33mmol) is dissolved in chloroform (3ml) and acetic acid (3ml), processes with N-bromosuccinimide (248mg, 1.40mmol), stirred at ambient temperature 30 minutes.By diluting careful quencher with saturated sodium bicarbonate (20ml), (3 * 20ml) extract with chloroform with reactant mixture.The organic facies that merges is washed dry (MgSO with saline (50ml)
4), vacuum evaporation obtains thick oil.Obtain subtitle compounds through preparation type TLC (hexane/ethyl acetate) purification, be oil.MS:ESI (anion): 302 (M-H).
B.) 2-(2-chloro-6-luorobenzyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With a) the 2ml anhydrous diethyl ether solution NiCl of product (144mg, 0.48mmol) of step
2(dppp) (3-5mol%) process, then drip at ambient temperature 2-chloro-6-luorobenzyl bromination magnesium (0.25M solution, 1.2mmol, 4.8ml) in 30 minutes.Reactant mixture is heated to reflux, kept 12 hours.Reactant mixture is cooled to ambient temperature, with 1M HCl (10ml) quencher, with diethyl ether (3 * 10ml) extractions.With ether extract water (30ml) washing that merges, dry (MgSO
4), evaporation obtains thick oil.Obtain subtitle compounds by the HPLC purification.C
18H
19ClFNO
2The MS value of calculation 369 of S+H, measured value 369.
C.) 2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use step b) product, by embodiment 3 step b) method prepare title compound.
1H NMR (300MHz, C
6D
6) δ 6.94 (d, J=8Hz, 1H), 6.52-6.70 (m, 2H), 6.49 (s, 1H), 4.17 (s, 2H), 2.47-2.78 (m, 8H), 2.03 (s, 1H) .MS:ESI (cation): 296 (M+H).
Embodiment 15.
3-bromo-2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine (flow process 3)
A.) 3-bromo-2-(2-chloro-6-luorobenzyl)-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 14 step b) product (49mg, 0.13mmol) is dissolved in CHCl
3In 1: 1 mixture (1mL) of/HOAc, process with sodium acetate (43mg, 0.52mmol) and N-bromosuccinimide (27mg, 0.15mmol).Reactant mixture is heated under 60 ℃, stirred 30 minutes.Reactant mixture is cooled to ambient temperature, and water (5ml) dilution is with chloroform (3 * 5ml) extractions.The organic extract that merges is washed dry (MgSO with 10%KOH
4), vacuum evaporation obtains subtitle compounds, is oil, and it is used without being further purified namely.
B.) 3-bromo-2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 3 step b) method prepare title compound.
1H?NMR(300MHz,C
6D
6)δ6.33-6.78(m,3H),4.09(s,2H),2.18-3.20(m,8H),1.62(s,1H)。C
15H
14The MS value of calculation 374 of BrClFNS+H, measured value 374.
Embodiment 16.
2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 4)
A.) (5-bromo-4-methylthiophene-2-yl)-hydroxyl-ethyl acetate:
2-bromo-3 methyl thiophene (13.2mL, 113mmol) is stirred in the 1L DCM of 0 ℃.Add oxalic acid chloroethene ester (ethylchloro oxalate) (13.9mL, 124mmol), then add AlCl
3(16.5g, 124mmol).Stir after 10 minutes, with reactant carefully to ice (~500mL) and EtOH (~300mL) on.When being warming up to room temperature, product is extracted in DCM (2x), use MgSO
4Dry.Concentrate and obtain the 37.5g orange solids, it is dissolved in THF (1L), with NaBH (OAc)
3(36g, 170mmol) processes.Be heated to 60 ℃ and keep to react cooling after 1 hour, with HOAc (13.6mL, 226mmol) quencher.Reactant is concentrated, and residue distributes between DCM/EtOH (5: 1) and water.Water layer is extracted (1x), the organic extract MgSO of merging with DCM
4Drying, concentrated, obtain subtitle compounds (35g), it is used without being further purified namely.
B.) (5-bromo-3-ethoxy carbonyl methyl-4-methylthiophene-2-yl)-ethyl acetate:
With a) product (~113mmol) use 300mL naphthalane, 103mL triethly orthoacetate (565mmol) and caproic acid (6.2mL, 50mmol) processing of step.Reactant is heated to 180 ℃ kept 10 minutes, and then add the 50mmol caproic acid.Heat after 10 minutes, add extra caproic acid (50mmol), reactant is heated again, kept 10 minutes.Reactant is cooling, and heating concentrates under vacuum, obtains subtitle compounds, is oil, and it is used without being further purified namely.
C.) 2-[5-bromo-3-(2-ethoxy)-4-methylthiophene-2-yl] ethanol:
With step b) product (~113mmol) be dissolved in EtOH (1L), be cooled to 0 ℃, then process with 170mL 2M NaOH.Stir after 24 hours, with the precipitate filtration of gained, use washing with alcohol, obtain the 15g disodium salt.This material part (3g, 8.9mmol) is dissolved in 90mL THF, with dioxane (4mL, the 16mmol) solution-treated of 4M HCl.After vigorous stirring 1/2 hour, add BH
3-THF (44.4mL, 1M) at room temperature stirred solution 2 hours.To react and use saturated NaHCO
3Careful quencher, concentrated.Thick residue is distributed between EtOAc and water (each 150mL).Organic layer MgSO
4Drying, concentrated, obtain the 1.94g subtitle compounds.
D.) 6-benzyl-2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step c) product (1.94g, 7.3mmol) is dissolved in 75mL DCM, is cooled to 0 ℃, uses Et
3N (29.3mmol, 4.1mL) processes, and then uses MsCl (22mmol, 1.71mL) to process.After 1 hour, add extra Et
3N and MsCl (being respectively 2eq and 1.5eq), then stirring reaction 1 hour.The crude reaction thing is poured on 5% citric acid, is extracted in DCM, use saturated NaHCO
3Washing.Organic solution MgSO
4After dry and concentrated, crude product is dissolved in dioxane (200mL), uses K
2CO
3(36.6mmol, 5.0g) processes.After being heated to reflux, add BnNH
2(22mmol, 2.4mL), back flow reaction is spent the night.Reactant is cooling, filter, concentrated.Subtitle compounds obtains the 419mg subtitle compounds by silica gel column chromatography (hexane solution of 10%EtOAc) purification.
E.) 2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With steps d) product (80mg, 0.24mmol) is dissolved in 2mL DCE.Add chloro-carbonic acid-2-chloroethene ester (103 μ L, 0.95mmol), at room temperature stirring reaction is 15 minutes.To react the quencher with 3mL MeOH, the crude reaction thing slightly is heated to reflux, and then is concentrated into dried.Thick residue is dissolved in 1/2mL MeOH, grinds with ether, obtain the 47mg title compound, be white solid.
1H NMR (CD
3OD) δ 3.36-3.30 (m, 4H), 3.12 (t, J=5.2Hz, 2H), 3.00 (t, J=5.1Hz, 2H), 2.11 (s, 3H); MS:ESI (cation): 246,248 (M+H).
Embodiment 17
3-methoxyl group-2-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 5)
A.) 5-oxo-azepan-Isosorbide-5-Nitrae-dicarboxylate:
4-oxo-piperidine-1-Ethyl formate (20g, 117mmol) is dissolved in 120mL Et
2In O, be cooled to-30 ℃.Added simultaneously BF in 30 minutes
3-OEt
2(14.8mL) and ethyl diazoacetate (16mL, 152mmol) (be dissolved in separately 15mL Et
2In O), internal temperature maintains approximately-20 ℃.Reactant is warming up to room temperature, stirred 3 hours, then will react and use 30%K
2CO
3(60mL) careful quencher.Organic layer K
2CO
3Drying, concentrated, obtain the 30.4g subtitle compounds.
B.) 3-hydroxyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-2, the 6-dicarboxylate:
With step a) product (20g, 77.8mmol) be dissolved in 300mL EtOH.Solution is cooled to 0 ℃, was blown into HCl gas 10 minutes in reaction.Add ethyl thioacetate (7.8mL, 77.8mmol), then be blown into HCl gas 3 minutes in solution.After at room temperature stirring 4 days, reactant is concentrated, use saturated NaHCO
3Neutralization is extracted in ether (200mL).Extract MgSO
4After dry and concentrated, residue is dissolved in EtOH (100mL), processes with NaOEt (the EtOH solution of 100mL 21%NaOEt).After stirring is spent the night, reactant with the dilution of 500mL water, is washed with 300mL DCM.DCM with the extraction of 150mL water, is then used 5%KOH (~10 * 75mL) extractions repeatedly.The water extract that merges with dense HCl acidify, is extracted into DCM (in 4 * 200mL).With DCM extract MgSO
4Drying, concentrated, obtain the 7.5g subtitle compounds, be oil.
C.) 3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-2, the 6-dicarboxylate:
With step b) product (2.3g, 7.3mmol) is dissolved in 1: 1 MeOH of 60mL: in THF.Add diisopropylethylamine (1.9mL, 10.9mmol), then add TMSCHN
2(10.9mL, 2M).At room temperature stirring reaction spends the night, and then carefully will react quencher with 0.4mL HOAc.Stir after 1/2 hour, reactant is distributed between DCM and 1M HCl (each 100mL).With organic layer MgSO
4Drying, concentrated, obtain the 2.75g subtitle compounds.
D.) 2-methylol-3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step c) product (2.5g, 7.8mmol) is dissolved in the anhydrous THF of 125mL, processes with LiCl (0.65g, 15.3mmol), then uses LiBH
4(15.3mL, 2M) processes.After stirring reaction 1 hour, carefully will react quencher with EtOH and HOAc, until no longer observed air release.Crude product mixture is distributed between water and DCM.With organic extract MgSO
4Drying, concentrated, obtain the limpid oil of 2.3g, it obtains the 1.03g subtitle compounds by silica gel column chromatography (30%EtOAc/ hexane) purification.
E.) 3-methoxyl group-2-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With steps d) product (70mg, 0.25mmol) is dissolved in 10mL EtOAc, processes with 35mg10%Pd/C (wet, Degussa E101 type), at H
2Under atmosphere, rapid stirring is 3 hours.Reactant is filtered, concentrated.Thick residue is dissolved in 1mL EtOH, processes with 1mL 40%KOH aqueous solution.After reactant is heated to 80 ℃ of maintenances and spends the night, dilute with water, with product extraction (2x) in DCM.Through preparation HPLC-MS purification, obtain title compound.
1H NMR (CDCl
3) δ 3.69 (s, 3H), 3.21-3.14 (m, 4H), 3.00 (t; J=5.2Hz, 2H), 2.88 (t, J=5.1Hz, 2H), 2.29 (s, 3H); MS:ESI (cation): 198 (M+H).
Embodiment 18.
2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 5)
A.) 3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-2,6-dioctyl phthalate 6-ethyl ester:
With embodiment 17 step c) product (1.0g, 3.19mmol) spends the night stirring in ethanol (20mL) together with 1M NaOH (6.38mL, 6.38mmol) under 80 ℃.Reactant is cooled to ambient temperature, and the acidify of 10%HCl solution is with the DCM solution extraction (x2) of 5%EtOH.Organic extract is merged, wash with water.With organic layer Na
2SO
4Drying is filtered, and is concentrated, obtains the 912mg subtitle compounds, and it is used without being further purified namely.MS:ESI (cation): 300 (M+H).
B.) 2-tert-butoxycarbonyl amino-3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) product (790mg, 3.01mmol) spend the night stirring in the tert-butyl alcohol (20mL) together with diphenylphosphine acyl azide (647 μ L, 3.01mmol) and triethylamine (418 μ L, 3.01mmol) under 80 ℃.Reactant is cooled to room temperature, pours saturated NaHCO into
3In aqueous solution.With gained mixture ethyl acetate extraction.With organic extract MgSO
4Drying obtains the 852mg subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification.MS:ESI (cation): 370 (M+H).
C.) 3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azacyclo-heptan-6-arboxylic acid:
With step b) product (256mg, 0.69mmol) stirred 30 minutes in TFA (2mL).Reactant is concentrated, be dissolved in EtOH (5mL).Add amyl nitrite (140 μ L, 1.04mmol) and Cu (OAc) in solution
2(188mg, 1.04mmol), at room temperature stirring reaction spends the night.Reactant is filtered the silicon dioxide plug, obtain the 17mg subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification.MS:ESI (cation): 271 (M+H).
D.) 2-bromo-3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step c) product (17mg, 0.067mmol) is dissolved in 1: 1 acetic acid of 1mL: CHCl
3In, process with N-bromosuccinimide (12mg, 0.068mmol).After 30 minutes, reaction solution is added drop-wise in saturated sodium bicarbonate solution, uses ethyl acetate extraction.Organic extract is concentrated, obtain subtitle compounds, it is used without being further purified namely.
E.) 2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Water (1mL) solution of 40%KOH is joined steps d) product is (in~0.067mmol) ethanol (1mL) solution.After being heated to 80 ℃ of maintenances and spending the night, reactant mixture is cooled to ambient temperature, distributes between water and DCM.Organic extract is concentrated, through preparation type LCMS purification, obtain title compound.
1H NMR (CD
3OD) δ 3.83 (s, 3H), 3.22-3.28 (m, 4H), 3.05 (t, J=5.1Hz, 2H), 2.93 (t, J=5.1Hz, 2H); MS:ESI (cation): 262 (M+H).
Embodiment 19.
2-chloro-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 5)
A.) 2-chloro-3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Use embodiment 18 step c) product and N-chlorosuccinimide, by embodiment 18 steps d) method prepare subtitle compounds.
B.) 2-chloro-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use a) product of step, by embodiment 18 step e) described method prepares title compound.
1H NMR (CD
3OD) δ 3.86 (s, 3H), 3.19-3.26 (m, 4H), 3.01 (t, J=5.4Hz, 2H), 2.88 (t, J=5.4Hz, 2H) .MS:ESI (cation): 218 (M+H).
Embodiment 20.
2-isopropenyl-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2 3d] azepine(flow process 5)
A.) 2-isopropenyl-3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 17 step c) product (59mg, 0.19mmol) is dissolved in 5mL THF, is cooled to 0 ℃.Add MeMgBr (0.54mL, 1.4M), at room temperature stirring reaction is 1 hour.To react water and HOAc (~3mL, 10: 1) quencher, be extracted into DCM (in 2 * 5mL).Organic extract is concentrated, obtain subtitle compounds, be oil, it is used without being further purified namely.
B.) 2-isopropenyl-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step a) product (~0.19mmol) with the EtOH and the processing of 40%KOH aqueous solution that be respectively 2mL.Be heated to 100 ℃ and keep after 16 hours, with the reactant dilute with water, product is extracted into DCM (in 2 * 4mL).Organic extract is concentrated, through preparation HPLC-MS purification title compound.
1H NMR (CD
3OD) δ 5.41 (s, 1H), 5.02 (t, J=1.6Hz, 1H), 3.14-3.08 (m, 4H), 2.96 (t, J=5.1Hz, 2H), 2.82 (t, J=5.1Hz, 2H), 2.09 (s, 3H); MS:ESI (cation): 224 (M+H).
Embodiment 21.
The 2-tert-butyl group-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 9)
A.) 3-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 16 step e) product (475mg, 1.68mmol) is dissolved in 50mL DCM, uses Et
3N (585 μ L, 4.2mmol) and ethyl chloroformate (210 μ L, 2.18mmol) are processed.After at room temperature stirring 3 days, reactant is concentrated on silica gel, obtains the 380mg urethanes by silica gel column chromatography (EtOAc/ hexane gradient) purification.Urethanes (60mg, 0.19mmol) is dissolved in 4mL EtOH, and the 10%Pd/C of use~10mg (wet, the DegussaE101 grade) processes, and stirs 12 hours under nitrogen atmosphere.Filter, concentrated, obtain subtitle compounds.
B.) the 2-tert-butyl group-3-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) product (37mg, 0.16mmol) stir in 1.5mL DCE.Add the tert-butyl alcohol (19uL, 0.20mmol), then add BF
3-OEt
2(20 μ L, 0.16mmol).Reactant is heated to 60 ℃ to be kept 1 hour.Concentrated, obtain subtitle compounds, it is used without being further purified namely.
C.) the 2-tert-butyl group-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step b) product is with the EtOH and the processing of 40%KOH aqueous solution that be respectively 2mL.Be heated to 100 ℃ and keep after 12 hours, reactant is cooling, dilute with water, extraction (2x) is in DCM.Title product is through preparation HPLC-MS purification.MS:ESI (cation): 224 (M+H).
Embodiment 22.
2-isopropyl-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 5)
A.) 2-isopropyl-3-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 20 steps a) product (35mg, 0.13mmol) be dissolved in 2mL EtOH, process with the 10%Pd/C of 50mg (wet, Degussa E101 grade).After stirring 3 hours under room temperature and nitrogen atmosphere, reactant is filtered, concentrated, obtain subtitle compounds, be oil.
B.) 2-isopropyl-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2J-d] azepine:
According to embodiment 20 step b) described method, with step a) product go the protection.Obtain title compound through preparation HPLC-MS purification.
1H NMR (CD
3OD) δ 3.69 (s, 3H), 3.29-3.21 (m, 5H), 3.03 (t, J=5.2Hz, 2H), 2.88 (t, J=5.4Hz, 2H), 1.24 (d, J=6.9Hz, 6H); MS:ESI (cation): 226 (M+H).
Embodiment 23.
2-bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 6)
A.) 4-methylene-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Diethylaminoethyl triphenyl phosphonium (6.3g, 17.6mmol) is dissolved in 150mL THF, is cooled to 0 ℃.Add KHMDS (3.2g, 16.2mmol), stirring reaction 1/2 hour in batches.With embodiment 1 step c) product (3.0g, 12.5mmol) adds with the form of 25mL THF solution.Reactant is warming up to room temperature, stirred 1 hour.Mixture is concentrated, and title product obtains the 2.6g subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification.
B.) 4-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) product (2.6g, 10.8mmol) be dissolved in 100mL EtOH, process with the 10%Pd/C of 0.5g (wet, Degussa E101 type).Rapid stirring after 14 hours, filters celite with reactant under nitrogen atmosphere, and is concentrated, obtains 2.3g subtitle chemical combination, is limpid oil.MS:ESI (cation): 240 (M+H).
C.) 2,3-two bromo-4-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step b) product (5.6g, 23.4mmol) is dissolved in the 250mL cyclohexane extraction, uses NaHCO
3(11.8g, 140mmol) processes.Slowly add bromine (3.6mL, 70.3mmol), at room temperature stirring reaction is 1/2 hour, then uses Na
2SO
3(180mL, 5% aqueous solution) quencher reaction.After rapid stirring 15 minutes, add EtOAc (~100mL), shift out organic layer, use MgSO
4Drying obtains the 9.1g subtitle compounds.Racemic material is used Chiral Technologies's
20 * 250mm post (10mL/min MeOH mobile phase) separates, and obtains enantiomer 1 (rt=9.8 minute) and the enantiomer 2 (rt=11.4 minute) of subtitle compounds.
D.) 4-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step c) product (800mg, 2.0mmol) is dissolved in 150mL EtOH, processes with the 10%Pd/C (wet, Degussa E101 grade) of 800mg.After stirring is spent the night, then add the Pd of 300mg, continue to stir 3 hours.Reactant is filtered celite, with DCM (300mL) dilution, water (1 * 300mL) washing.With organic layer MgSO
4Drying, concentrated, obtain the 475mg subtitle compounds.
E.) 2-bromo-4-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With steps d) product (80mg, 0.35mmol) is dissolved in 1: 1 CHCl of 2mL
3In/HOAc.Add N-bromosuccinimide (62mg, 0.35mmol), stirring reaction 15 minutes.Concentrated, by the silica gel column chromatography purification, obtain subtitle compounds, be yellow oil.
F.) 2-bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
According to embodiment 20 step b) described method, with step e) product go the protection, obtain title compound.
1H NMR (CD
3OD) δ 6.97 (s, 1H), 3.46-3.11 (m, 7H), 1.39 (d, J=7.2Hz, 3H); MS:ESI (cation): 246,248 (M+H).
Embodiment 24.
2-bromo-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 7)
A.) 2-thiene-3-yl--ethamine:
Thiene-3-yl--acetonitrile (5.0g, 40.6mmol) is dissolved in 50mL THF.Slowly add BH
3-THF (61mL, 1M THF solution).Reactant is heated to 60 ℃ of maintenances spends the night, then use the careful quencher of 4%HCl aqueous solution, until do not observe the bubbling phenomenon.Then crude product mixture is distributed between EtOAc and water (being respectively 300mL).Water layer is acidified to pH~12 with 30%NaOH, product be extracted into DCM/EtOH (4: 1,3x) in.With organic extract MgSO
4Drying, concentrated, obtain the 2.9g subtitle compounds, be oil.
B.) [ethoxy carbonyl-(2-thiene-3-yl--ethyl)-amino]-ethyl acetate:
Use a) described method of embodiment 1 step, from step a) product prepare subtitle compounds.
C.) [ethoxy carbonyl-(2-thiene-3-yl--ethyl)-amino]-acetic acid:
Use embodiment 1 step b) described method, from step b) product prepares subtitle compounds.
D.) 8-oxo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Use embodiment 1 step c) described method, from step c) product prepares subtitle compounds.
E.) 8-methylene-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With MePPh
3Br (785mg, 2.2mmol) is dissolved in 7mL THF, processes with KHMDS (408mg, 2.04mmol).Stirring after 30 minutes, with steps d) product (350mg, 1.5mmol) adds with the form of 3mL THF solution.Stir after 1 hour, reactant is diluted with EtOAc, wash with water.Organic layer is concentrated, and product obtains the 188mg subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification.
F.) 8-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3 ,-d] azepine-6-Ethyl formate:
With step a) product (59mg, 0.25mmol) be dissolved in 5mL EtOH, process with the 10%Pd/C of 75mg (wet, Degussa E101 grade).Stir under nitrogen atmosphere after 1 hour, reactant is filtered, concentrated, obtain subtitle compounds, it uses without being further purified namely.
G.) 2-bromo-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step f) product is dissolved in 1: 1 CHCl of 2mL
3In/HOAc, process with NBS (62mg, 0.35mmol).Stir after 10 minutes, reactant is concentrated into dried, filter silicagel pad, use the EtOAc eluting.Eluent is concentrated, and residue is processed with the EtOH and the 40%KOH aqueous solution that are respectively 2mL.After 14 hours, with the reactant dilute with water, extraction (2x) is in DCM in heating under 100 ℃.Title compound carries out purification through preparation HPLC-MS.With Chiral Technologies's
20 * 250mm post (10mL/min MeOH mobile phase) is isolated two kinds of enantiomers, namely obtains enantiomer 1 (rt=11.6 minute) and the enantiomer 2 (rt=13.6 minute) of title compound.
1H NMR (CD
3OD) δ 6.92 (s, 1H), 3.48-3.34 (m, 3H), 3.17-2.99 (m, 4H), 1.44 (d, J=7.2Hz, 3H); MS:ESI (cation): 246,248 (M+H).
Embodiment 25.
2-bromo-8-Spirocyclopropyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 7)
A.) 8-Spirocyclopropyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With ZnCl
2(2.49mL, 1M hexane solution) and CH
2I
2(100 μ L, 1.24mmol) stirred 30 minutes in DCM under 0 ℃.With embodiment 24 step e) product (59mg, 0.25mmol) adds with the form of DCM solution (1mL), and stirring reaction is 48 hours at ambient temperature.With the reactant dilute with water, be extracted in DCM.With the saturated NH of organic layer
4Cl, water and salt water washing.Organic layer is concentrated, obtain subtitle compounds, it is used without being further purified namely.MS:ESI (cation): 252 (M+H).
B.) 2-bromo-8-Spirocyclopropyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Use a) product of step, by embodiment 18 steps d) described method prepares subtitle compounds, and it is used with the crude product form without purification.MS:ESI (cation): 330 (M+H).
C.) 2-bromo-8-Spirocyclopropyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use step b) product, by embodiment 18 step e) described method prepares title compound.
1H NMR (CD
3OD) δ 6.84 (s, 1H), 3.20 (t, J=5.1Hz, 2H), 3.02 (t, J=5.1Hz, 2H), 3.06 (s, 2H), 1.08 (d, J=9.6Hz, 2H), 1.05 (d, J=9.6Hz, 2H) .MS:ESI (cation): 258 (M+H).
Embodiment 26.
2-(pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 8)
A.) 2-chlorosulfonyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 1 steps d) product (400mg, 1.8mmol) is dissolved in 10mL CHCl
3In, process with chlorosulfonic acid (355 μ L, 1.8mmol).After 5 minutes, will react in quencher on ice, be extracted into immediately DCM (in 2 * 10mL).Organic extract MgSO
4Drying, concentrated, obtain the 200mg subtitle compounds, be solid, it is used without being further purified namely.
B.) 2-(pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step a) product (45mg, 0.14mmol) at 2mL CHCl
3Middle stirring is processed with pyrrolidine (46 μ L, 0.55mmol).Stir after 5 minutes, reactant is concentrated into dried, residue is dissolved in respectively in the EtOH of 2mL and 40%KOH aqueous solution.Reactant being heated to 100 ℃ of maintenances in hermetic container spends the night.After cooling, with the reactant dilute with water, product is extracted into DCM (in 4 * 3mL).Organic extract is concentrated, and title compound carries out purification through preparation HPLC-MS.
1H NMR (CD
3OD) δ 7.42 (s, 1H), 3.43-3.34 (m, 4H), 3.31-3.24 (m, 6H), 3.13 (t, J=5.2Hz, 2H), 1.81-1.76 (m, 4H); MS:ESI (cation): 287 (M+H).
Embodiment 27.
N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide(flow process 8)
Use Dimethylammonium chloride and Et
3N is according to embodiment 26 step b) described method prepares title compound.
1H NMR (CD
3OD) δ 7.38 (s, 1H), 3.44-3.27 (m, 4H), 3.32-3.26 (m, 2H), 3.17-3.14 (m, 2H), 2.72 (s, 6H); MS:ESI (cation): 261 (M+H).
Embodiment 28.
3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonic acid diacetayl amide(flow process 8)
A.) 2-chlorosulfonyl-3-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Use a) intermediate of gained of embodiment 21 steps, according to embodiment 26 steps a) described method prepare subtitle compounds.Product is used without being further purified namely.
B.) N, N-dimethyl-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide:
Use step a) product and Dimethylammonium chloride and Et
3N is according to embodiment 26 step b) described method prepares title compound.
1H NMR (CD
3OD) δ 3.41-3.35 (m, 4H), 3.24 (dd, J=5.1,6.6Hz, 2H), 3.04 (t, J=5.2Hz, 2H), 2.75 (s, 6H), 2.41 (s, 3H); MS:ESI (cation): 275 (M+H).
Embodiment 29.
5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-formic acid ring pentanamide(flow process 8)
A.) 2-cyclopenta carbamoyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 1 steps d) product (50mg, 0.222mmol) and isocyano network Pentamethylene. (25 μ L, 0.222mmol) and AlCl
3(35mg, 0.266mmol) stirred 4 hours in dichloroethanes (2mL) together at ambient temperature.Add again isocyano network Pentamethylene. (25 μ L, 0.222mmol) and AlCl
3(35mg, 0.266mmol), stirring reaction spends the night.Reactant is distributed between water and DCM.Organic layer is washed with water, concentrated, obtain subtitle compounds, it is used without being further purified namely.MS:ESI (cation): 337 (M+H).
B.) 5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-formic acid ring pentanamide:
With step b) product (37mg, 0.111mmol) DCM (2mL) solution-treated of TMSI (50 μ L, 0.333mmol), stir under 50 ℃ and spend the night.Then reactant is processed with methanol (1mL), be concentrated into driedly, through preparation type LC-MS purification, obtain title compound.MS:ESI (cation): 265 (M+H).
Embodiment 30.
N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-Methanamide(flow process 8)
A.) 2-formyl-dimethylamino-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 1 steps d) product (50mg, 0.22mmol) under 75 ℃ with dichloro methylene alkyl dimethyl ammonium chloride (84mg, 0.518mmol) and AlCl
3(35mg, 0.266mmol) stirs in dichloroethanes together and spends the night.Reaction is cooled to ambient temperature, and water (2mL) quencher is extracted in DCM.Then make organic layer by the celite pad, concentrated, obtain subtitle compounds, it is used without being further purified namely.MS:ESI (cation): 297 (M+H).
B) N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-Methanamide:
Use a) product of step, by embodiment 29 step b) described method prepares title compound.MS:ESI (cation): 225 (M+H).
Embodiment 31.
(R, S)-2-chloro-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 7)
Use embodiment 24 step g) method, from embodiment 24 step f) described intermediate and N-chlorosuccinimide prepare title compound.MS:ESI (cation): 202,204 (M+H).
Embodiment 32.
2,3-, two bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 6)
By embodiment 20 step b) described method, with embodiment 23 step c) product go the protection, obtain title compound.
1H NMR (CD
3OD) δ 3.60-3.52 (m, 3H), 3.35-3.11 (m, 4H), 1.33 (d, J=6.9Hz, 3H); MS:ESI (cation): 324,326,328 (M+H).
Embodiment 33.
(R, S)-2-bromo-4-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 6)
A.) (R, S)-4-hydroxyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Sodium borohydride (154mg, 4.18mmol) is joined embodiment 1 step c) in ethanol (2mL) solution of product (200mg, 0.837mmol), stirred at ambient temperature 30 minutes.To react and use the acetic acid quencher, reactant distributes between DCM and water.Organic layer is washed with water, concentrated, obtain subtitle compounds, it is used without being further purified namely.MS:ESI (cation): 264 (M+Na).
B.) (R, S)-4-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) anhydrous THF (2.0mL) solution of product (160mg, 0.664mmol) be cooled to-78 ℃.Add THF (800 μ L, the 0.797mmol) solution of 1M LHMDS to this solution, reactant is warming up to room temperature.Add MeI (63 μ L, 0.996mmol) in reactant, stirred at ambient temperature 72 hours.Reactant is distributed between ethyl acetate and water, and concentrated organic layer obtains subtitle compounds, first passes through silica gel column chromatography (EtOAc/ hexane gradient) purification before it uses in following steps.MS:ESI (cation): 278 (M+Na).
C.) (R, S)-2-bromo-4-methoxyl group-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Use step b) product, by embodiment 18 steps d) method prepare subtitle compounds.
D.) (R, S)-2-bromo-4-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use step c) product, by embodiment 18 step e) method prepare title compound.MS:ESI (cation): 262 (M+H).
Embodiment 34.
2-bromo-8,8-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 7)
A.) 8,8-dimethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate
DCM (5mL) is cooled to-78 ℃, uses TiCl
4(274 μ L, 2.5mmol) processes, and then uses Me
2Zn (the 2M toluene solution of 1.3mL) processes.With this dark red solution after stirring 15 minutes under-78 ℃, with embodiment 24 steps d) product (100mg, 0.42mmol) slowly adds with the form of 5mLDCM solution.Reactant is warming up to 0 ℃, stirred 2 hours.To react in quencher on ice, product is extracted in DCM (2x).With organic extract MgSO
4Drying, concentrated, obtain subtitle compounds, it is used without being further purified namely.
B.) the 2-bromo-8,8-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine
With step a) product (45mg, 0.18mmol) be dissolved in 1: 1 HOAc/CHCl of 4mL
3In, process with NBS (44mg, 0.25mmol).Stir after 1/2 hour, reactant is concentrated into dried, with the EtOH and the processing of 40%KOH aqueous solution that be respectively 2mL.Mixture heated to 100 a ℃ maintenance is spent the night, cooling, dilute with water.Product extraction (2x) (in 2 * 4mL), is concentrated, through preparation HPLC-MS purification to DCM.
1H
(cation)
NMR(CD
3OD)δ7.19(s,1H),3.40-3.34(m,2H),3.28(s,2H),3.21-3.17(m,2H)?1.41(s,6H);MS:ESI:260,262(M+H).
Embodiment 35.
(R, S)-2-bromo-4-ethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 9)
A.) (E, Z)-4-ethylidene-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
KHMDS (233mg, 1.17mmol) is joined in THF (5mL) solution of bromination (ethyl) triphenyl phosphonium (466mg, 1.26mmol) that is cooled to 0 ℃ gained solution stirring 20 minutes.Add embodiment 1 step c in reactant) THF (5mL) solution of product (200mg, 0.837mmol), in 1 hour, reactant is warming up to room temperature.To react the water quencher, reactant distributes between ethyl acetate and water.Organic layer is concentrated, and crude product obtains the 151mg subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification, is the mixture of E isomer and Z isomer.MS:ESI (cation): 252 (M+H).
B.) (R, S)-4-ethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) product (151mg, 0.602mmol) at H
2(1atm) the lower stirring in ethanol (3mL) together with 10%Pd/C (50mg) spent the night.Reactant is filtered celite, be concentrated into driedly, obtain the 131mg subtitle compounds, be violet oil, it is used without being further purified namely.MS:ESI (cation): 254 (M+H).
C.) (R, S)-2-bromo-4-ethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Use step b) product, by embodiment 18 steps d) method prepare subtitle compounds, it is not purified is namely used with the crude product form.
D.) (R, S)-2-bromo-4-ethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
Use embodiment step c) product, by embodiment 18 step e) described method prepares title compound.
1H NMR (CD
3OD) δ 6.88 (s, 1H), 3.19-3.28 (m, 3H), 2.92-3.15 (m, 4H), 1.61-1.84 (m, 2H), 0.98 (t, J=7.3Hz, 3H) .MS:ESI (cation): 260 (M+H).
Embodiment 36.
2-bromo-3,4-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 9)
A.) 3-bromo-4-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 23 step c) product (enantiomer 2,0.75g, 1.9mmol) and Zn (0.25g, 3.8mmol) be respectively to be heated to reflux in the water of 20 mL and HOAc.After 1/2 hour, reactant is cooling, with the EtOAc dilution, wash (2x) with water.With organic layer MgSO
4Drying, concentrated, obtain the 490mg subtitle compounds, be oil, it is used without being further purified namely.
B.) 3,4-dimethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate
With step a) product (150mg, 0.47mmol) be dissolved in the 3mL dioxane, use Me
2Zn (the 2M toluene solution of 0.47mL) and Pd (ddf)
2Cl
2(11mg, 0.014mmol) processes.Be heated to 100 ℃ and keep to react the water quencher after 3 hours, filter.With filtrate between EtOAc and water (being respectively 7mL) distribute.Organic layer MgSO
4Drying, concentrated, obtain the 92mg subtitle compounds, it is used without being further purified namely.
C.) the 2-bromo-3,4-dimethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate
With step b) product (92mg, 0.36mmol) is dissolved in 1: 1 HOAc/CHCl of 4mL
3In, process with NBS (67mg, 0.38mmol).Stir after 1/2 hour, with reactant with EtOAc (70mL) dilution, water (3 * 30mL) and 1M NaOH (2 * 30mL) washing.With organic solution MgSO
4Drying, concentrated.Crude product obtains the 90mg subtitle compounds by silica gel column chromatography (EtOAc/ hexane gradient) purification.
D.) the 2-bromo-3,4-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine
With step c) product is by embodiment 20 step b) describedly go protection.Obtain title compound after preparation HPLC-MS purification.
1HNMR (CD
3OD) δ 3.59-3.08 (m, 7H), 2.13 (s, 3H), 1.31 (d, J=7.2Hz, 3H); MS:ESI (cation): 260,262 (M+H).
*Enantiomer 1 can prepare in a similar manner.
Embodiment 37.
2-bromo-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene(flow process 10)
a.)
(E, Z)-4-ethoxy carbonyl methylene-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
THF (15mL) solution that adds 1.6M LHMDS in anhydrous THF (100mL) solution of phosphonoacetic acid triethyl (4mL, 16.74mmol).Mixture was stirred 15 minutes, then adds embodiment 1 step c) product (2.0g, 8.37mmol).To react to stir and spend the night, and then use extra LHMDS solution (3.2mL, 1.6M) and phosphonoacetic acid triethyl (800 μ L, 3.3mmol) to process.Stir after 3 hours, will react the water quencher, dilute with DCM.With organic layer MgSO
4Drying, concentrated, obtain subtitle compounds, it is used without being further purified namely.MS:ESI (cation): 310 (M+H).
b.)
(R, S)-4-ethoxy carbonyl methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) product (2.47g, 8mmol) at H
2(1atm) lower and 2.0g 10%Pd/C (wet, Degussa E101 grade) stirred 72 hours in methanol (8mL) together.Reactant is filtered celite, be concentrated into driedly, obtain subtitle compounds, be oil, it is used without being further purified namely.MS:ESI (cation): 312 (M+H).
c.)
(R, S)-4-carboxymethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step b) product (2.47g, 8mmol) stirs in ethanol (60mL) together with 1M NaOH (30mL) at ambient temperature and spends the night.Reactant with 1M HCl acidify, is distributed between DCM and water.Organic layer is washed with water, use MgSO
4Drying is concentrated into driedly, obtains the 2.13g subtitle compounds, is yellow oil, and it is used without being further purified namely.MS:ESI (cation): 284 (M+H).
d.)
(R, S)-3-oxo-3,4,4a, 5,7,8-, six hydrogen-1-thia-6-azepine-cyclopenta [cd] azulene-6-Ethyl formate:
The DMF of oxalyl chloride (3mL, 37.7mmol) and catalytic amount is joined step c) in DCM (40mL) solution of product (2.13g, 7.54mmol), stirring reaction is 1 hour at ambient temperature.Reactant is concentrated into dried, heavily is dissolved in dichloroethanes (100mL).With AlCl
3(2.0g, 15.1mmol) joins in solution, and stirring reaction spends the night at ambient temperature.To react with the ice quencher, distribute between DCM and water.Organic layer is concentrated, obtain subtitle compounds, before using, it first passes through silica gel column chromatography (the EtOAc/ hexane gradient is isolated 1.02g) purification in following steps.MS:ESI (cation): 266 (M+H).
E.) (R, S)-3,4,4a, 5,7,8-, six hydrogen-1-thia-6-azepine-cyclopenta [cd] azulene-6-Ethyl formate:
With AlCl
3(627mg, 4.72mmol) joins the BH of 0 ℃
3TBuNH
2In the DCM of (492mg, 5.66mmol) (2mL) solution.With solution stirring 10 minutes, then use steps d) product (250mg, 0.943mmol) is with the formal layout of DCM (1mL) solution.After being warming up to room temperature, dripping 0.1M HCl and will react quencher, reactant is concentrated into dried.Reactant with 1M HCl dilution, is extracted in EtOAc.Organic layer is concentrated, obtain subtitle compounds, before using, it first passes through silica gel column chromatography (EtOAc/ hexane gradient) purification in following steps.MS:ESI (cation): 252 (M+H).
f.)
(R, S)-2-bromo-3,4,4a, 5,7,8-, six hydrogen-1-thia-6-azepine-cyclopenta [cd] azulene-6-Ethyl formate:
Use step e) product, by embodiment 18 steps d) method prepare subtitle compounds, it is not purified is namely used with the crude product form.
G.) the 2-bromo-4,4a, and 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene:
Use step f) product, by embodiment 18 step e) method prepare title compound, through preparation HPLC-MS purification in addition.With Chiral Technologies's
AD-
20 * 250mm post (10mL/min MeOH mobile phase) is isolated two kinds of enantiomers, namely obtains enantiomer 1 (rt=8.6 minute) and the enantiomer 2 (rt=10.8 minute) of title compound.
1H NMR (CD
3OD) δ 3.45-3.56 (m, 2H), 2.89-3.08 (m, 3H), 2.45-2.65 (m, 4H), 1.99-2.04 (m, 2H) .MS:ESI (cation): 260 (M+H).
Embodiment 38.
(R, S)-2-methyl-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene:(flow process 10)
A.) (R, S)-2-methyl-3,4,4a, 5,7,8-, six hydrogen-1-thia-6-azepine-cyclopenta [cd] azulene-6-Ethyl formate:
With 2M Me
2The toluene solution of Zn (1.5mL) joins embodiment 37 step f) product (50mg, 0.150mmol) and Pd (dppf)
2Cl
2In the dioxane of (4mg, 0.0045mmol) (1mL) solution.Heat 100 ℃ after keep 3 hours, will react the water quencher, reactant is extracted in ethyl acetate.Organic layer is merged, concentrated, obtain subtitle compounds, it is not purified is namely used with the crude product form.MS:ESI (cation): 266 (M+H).
b.)
(R, S)-2-methyl-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene:
Use a) product of step, by embodiment 18 step e) described method prepares title compound, through preparation HPLC-MS purification in addition.
1H NMR (CD
3OD) δ 3.52-3.64 (m, 2H), 325-3.30 (m, 1H), 2.86-3.10 (m, 4H), 2.46-2.73 (m, 4H), 2.23 (s, 3H) .MS:ESI (cation): 194 (M+H).
Embodiment 39.
The 2-tert-butyl group-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene:(flow process 10)
a.)
(R, S)-2-tert-butyl group-3,4,4a, 5,7,8-, six hydrogen-1-thia-6-azepine-cyclopenta [cd] azulene-6-Ethyl formate:
With embodiment 37 step e) product (100mg, 0.398mmol), BF
3OEt (50 μ L, 0.398mmol) and the tert-butyl alcohol (56 μ L, 0.597mmol) are heated to 75 ℃ and kept 2 hours in dichloroethanes (1mL).To react the water quencher, reactant is extracted in DCM.Organic layer is merged, spend the night concentrated, obtain subtitle compounds, it is not purified is namely used with the crude product form.MS:ESI (cation): 308 (M+H).
B.) the 2-tert-butyl group-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene:
Use a) product of step, by embodiment 18 step e) described method prepares title compound.With Chiral Technologies's
AD-
20 * 250mm post (10 mL/min MeOH mobile phase) is isolated two kinds of enantiomers, namely obtains enantiomer 1 (rt=7.7 minute) and the enantiomer 2 (rt=10.2 minute) of title compound.
1H NMR (CD
3OD) δ 3.20-3.34 (m, 2H), 2.91-3.01 (m, 1H), (2.56-2.91 m, 5H), 2.27-2.39 (m, 2H), (1.74-1.88 m, 1H), 1.30 (s, 9H) .MS:ESI (cation): 236 (M+H).
Embodiment 40.
2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1a)
A.) the 2-iodo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 1 steps d) CHCl of product (470mg, 2.09mmol)
3(5ml) and AcOH (5ml) solution process with N-iodosuccinimide (493mg, 2.19mmol) under 22 ℃.After 1 hour, with reactant CH
2Cl
2(20ml) dilution, pour saturated NaHCO into
3(20ml).(1 * 20ml) washs, dry (MgSO with saline with organic layer
4), concentrated, obtain thick subtitle compounds, be yellow oil, it is used without being further purified namely.
B.) 2-trifluoromethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a.) product (75mg, 0.21mmol) DMF (0.5ml) and NMP (0.5ml) solution with bipyridyl (43mg, 0.27mmol), CuI (44mg, 0.23mmol), KF (13mg, 0.23mmol) and trimethyl silyl fluoroform (2.1ml, 1.05mmol) processing.Reactant mixture is heated to 80 ℃ to be kept 3 days.Reactant is cooling, filter celite, with EtOAc (20ml) washing.(2 * 3ml) wash, dry (MgSO with saline with eluent
4), obtain subtitle compounds, be brown oil, it is used without being further purified namely.
C.) 2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step b.) CH of crude product (26mg, 0.089mmol)
2Cl
2(0.5ml) solution was processed 12 hours with iodo three monosilanes (19 μ l, 0.134mmol) under 50 ℃.Add MeOH will react quencher, evaporating solvent.Residue obtains title compound through preparation type LC/MS purification.
NMR (300MHz, CDCl
3) δ 7.18 (s, 1H); (3.42-3.56 m, 6H); (3.31-3.39 m, 2H), 2.09 (s, 1H); MS:ESI (cation): 222 (M+H).
Embodiment 41.
3-chloro-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1b)
A.) 2,3-two chloro-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 4 step H) CH of product (323mg, 1.25mmol)
2Cl
2(6.25ml) solution is cooled to 0 ℃, adds triethylamine (522 μ l, 3.75mmol), then adds ethyl chloroformate (144 μ l, 1.5mmol).1.5 after hour, reactant is poured in water (25ml), with EtOAc (50ml) dilution.With the dry (MgSO of organic layer
4), concentrated, obtain 341mg (93%) subtitle compounds, it is used without being further purified namely.MS:ESI (cation): 294,296 (M+H).
B.) 3-chloro-2-iodo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a) anhydrous THF (2.2ml) solution of product (129mg, 0.44mmol) be cooled to-78 ℃, process with the n-BuLi (412 μ l, 0.66mmol) of 1.5 equivalents.After 1 hour, will react and use I
2The THF solution quencher of (167mg, 0.66mmol).Reactant is warming up to 22 ℃, with EtOAc (15ml) dilution.With the saturated NaSO of organic layer
3(5ml), saline (5ml) washing, dry (MgSO
4), obtaining the thick subtitle compounds of 98mg (58%), it is used without being further purified namely.MS:ESI (cation): 386 (M+H).
C.) 3-chloro-2-trifluoromethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step b) product (140mg, 0.363mmol) NMP (0.9ml) and DMF (0.9 ml) solution with CuI (76mg, 0.39mmol), KF (46.4mg, 0.79mmol), bipyridyl (74mg, 0.472mmol) and TMSCF
3(267 μ l, 1.81mmol) processes.With mixture heated to 80 ℃ maintenance 12 hours.Crude product mixture is diluted with EtOAc, filter celite.With organic facies H
2O (2 * 1ml), saline (1 * 1ml) washing, dry (MgSO
4), concentrated.Crude product through preparation type TLC purification, obtains 14.4mg (12.1%) subtitle compounds with 10: 1 hexane/EtOAc.
D.) 3-chloro-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step c) CH of product (14.4mg, 0.044mmol)
2Cl
2(220 μ l) solution was processed 12 hours with iodo three monosilanes (19 μ l, 0.13mmol) under 60 ℃.Add MeOH will react quencher, evaporating solvent.Residue obtains 2.3mg (18%) title compound through preparation type LC/MS purification.MS:ESI (cation): 256 (M+H).
Embodiment 42.
3-bromo-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 1b)
A.) the 3-bromo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 3 steps a) AcOH of product (148mg, 0.39mmol) (80 μ l) and H
2O (1.92ml) solution was processed 4.5 hours with Zn (76mg, 1.17mmol) under 105 ℃.Then, content is cooled to 22 ℃, pours saturated NaHCO into
3(25ml), with EtOAc (2 * 25ml) extractions.With the dry (MgSO of organic layer
4), concentrated, obtain 80mg (68%) subtitle compounds, it is used without being further purified namely.
B.) 3-bromo-2-iodo-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With a) CHCl of product (124mg, 0.41mmol) of step
3(1.0ml) and AcOH (1.0ml) solution processed 30 minutes with N-iodosuccinimide (97mg, 0.43mmol).Then, pour the crude reaction thing into saturated NaHCO
3(5ml), use CH
2Cl
2(2 * 4ml) extractions.With the saturated NaHCO of organic layer
3(3ml) washing, dry (extrelut post), concentrated, (80% hexane: 20%EtOAc) purification obtains 134mg (76%) subtitle compounds through preparation type TLC.
C.) 3-bromo-2-trifluoromethyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step b) product (134mg, 0.31mmol) NMP (1ml) and DMF (1ml) solution under 50 ℃ with KF (20mg, 0.34mmol), CuI (65mg, 0.34mmol) and bipyridyl (62mg, 0.4mmol) processed 15 minutes.Then, add the 0.5M solution of trimethyl silyl fluoroform (3.1ml, 1.55mmol), reactant mixture was stirred 16 hours under 80 ℃.Reactant mixture is cooled to 22 ℃, uses CH
2Cl
2(5ml) dilution is with saline (10ml) washing.With water layer CH
2Cl
2(3 * 5ml) extractions, the organic layer dry (extrelut post) that merges is concentrated by silica gel plug, through preparation type LC/MS purification, obtain 26mg (23%) subtitle compounds.
D.) 3-bromo-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step c) CH of product (51mg, 0.137mmol)
2Cl
2(685 μ l) solution was processed 16 hours with iodo three monosilanes (59 μ l) under 50 ℃.Add MeOH will react quencher, evaporating solvent.Residue obtains 16mg (39%) title compound through preparation type LC/MS purification.
NMR (300MHz, CDCl
3) δ 4.10-4.40 (br s, 1H); (2.90-3.60 m, 8H) .MS:ESI (cation): 300,302 (M+H).
Embodiment 43.
3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 3)
A.) 3-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With a) anhydrous THF (2ml) the solution NiCl of product (122mg, 0.40mmol) of embodiment 42 steps
2(dppp) (2-3mg, 0.004mmol) processes, and then drips 1.4M methylmagnesium-bromide (0.71ml, 1mmol) solution under 22 ℃, and then back flow reaction is 16 hours.Reactant mixture is cooled to 22 ℃, with ether (5ml) dilution, with 1N HCl (2ml) quencher.(3 * 5ml) strip with ether with water layer.With organic extract water (10ml) washing that merges, dry (MgSO
4).Evaporating solvent obtains thick subtitle compounds, is sepia oil, and it is used without being further purified namely.
B.) 3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine
With a) CH of product of step
2C1
2(1ml) solution is used iodo three silane treated 16 hours under 50 ℃.Add MeOH will react quencher, evaporating solvent.Residue obtains the 1.6mg title compound through preparation type LC/MS purification.
NMR (300MHz, CDCl
3) δ 6.69 (d, J=1Hz, 1H); (4.8-5.2 br s, 1H); (3.20-3.40 m, 6H); (3.00-3.1 m, 2H); (2.14 d, J=1Hz, 3H); MS:ESI (cation): 168 (M+H).
Embodiment 44.
The 2-tert-butyl group-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 5)
A.) the 2-tert-butyl group-3-methyl-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
Embodiment 18 steps under stir a) add the tert-butyl alcohol (25 μ L, 0.26mmol) in the 0.5mLDCE solution of product (20mg, 0.078mmol), then add BF
3-OEt
2(10 μ L, 0.078mmol).Reactant is heated to 75 ℃ to be kept 2 hours.Allow reactant be cooled to room temperature, be concentrated into driedly, residue is used without being further purified namely.MS:ESI (cation): 312 (M+H).
B.) the 2-tert-butyl group-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine:
With step a) product with the EtOH and the processing of 40%KOH aqueous solution that be respectively 0.5mL.Be heated to 100 ℃ and keep after 18 hours, reactant is cooling, and dilute with water is extracted into DCM (in 2 * 10ml).Organic layer is concentrated into dried, residue obtains title compound through preparation HPLC-MS purification.
1H NMR (300MHz, CD
3OD) δ 3.78 (s, 3H); (3.30-3.38 m, 4H); (3.06-3.15 m, 2H); (2.94-3.03 m, 2H); (1.45 s, 9H) .MS:ESI (cation): 240 (M+H).
Embodiment 45.
The 2-tert-butyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 9)
Embodiment 1 steps d under stir) add the tert-butyl alcohol (36 μ L, 0.38mmol) and BF in the 2.5mLDCE solution of product (66mg, 0.29mmol)
3-OEt
2(36 μ L, 0.29mmol).Reactant is heated to 60 ℃ to be kept 2 hours.Reactant is concentrated into dried, with the EtOH and the processing of 40%KOH aqueous solution that be respectively 2mL.Mixture heated to 100 a ℃ maintenance is spent the night, cooling, dilute with water.Product is extracted into DCM (in 2 * 10mL), to be concentrated, through preparation HPLC-MS purification, obtains title compound.MS:ESI (cation): 210 (M+H).
Embodiment 46.
The 2-tert-butyl group-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 4)
Embodiment 47.
3-chloro-2-(1,1,3,3-tetramethyl butyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 4)
Embodiment 48.
3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine(flow process 4)
Embodiment 46 embodiment 47 embodiment 48
A.) the 3-chloro-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With embodiment 41 step a.) THF (6.5ml) solution of product (382mg, 1.3mmol) is cooled to-78 ℃, with 1.6M n-BuLi (2.26ml, 1.36mmol) solution-treated.After 1 hour, will react the water quencher, with EtOAc (2 * 30ml) extractions.(1 * 15ml) washs, dry (MgSO with saline with organic layer
4), concentrated.Thick yellow through silica gel column chromatography (EtOAc/ hexane gradient) purification, obtain 156mg (46%) subtitle compounds.
1H?NMR(300MHz,CDCl
3)δ6.88(s,1H);4.19(q,J=7Hz,2H);3.57-3.72(m,4H);2.92-3.03(m,2H);2.81-2.92(m,2H);1.29(t,J=7Hz,3H).
B.) the 2-tert-butyl group-3-chloro-4,5,7,8-tetrahydrochysene-thieno [2,3-d] azepine-6-Ethyl formate:
With step a.) dichloroethanes (3ml) solution of product (156mg, 0.6mmol) is with t-BuOR (172 μ l, 1.8mmol) and BF
3-OEt
2(113 μ l, 0.9mmol) processes.Reactant mixture is heated to 85 ℃ kept 6 hours, then evaporating solvent, obtain thick subtitle compounds.
C.) the 2-tert-butyl group-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine, embodiment 44; 3-chloro-2-(1,1,3,3-tetramethyl butyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine, embodiment 45; 3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine, embodiment 46:
With step b.) Tetrabutylammonium bromide (20mg) processing of the solution of crude product in EtOH (4ml) and 40%KOH aqueous solution (4ml), and be heated to 95 ℃ of maintenances 2 days.Then, reactant is cooled to 22 ℃, uses CH
2Cl
2(3 * 25ml) extractions.(1 * 10ml) washs, dry (MgSO with saline with organic layer
4), be concentrated into dried.Residue obtains subtitle compounds through preparation type LC/MS purification.
(A)
1H NMR (300MHz, CDCl
3) δ 6.50-6.80 (br s, 1H); (3.05-3.14 m, 4H); (2.87-2.99 m, 4H); (1.43 s, 9H); MS:ESI (cation): 244 (M+H); (B)
1H NMR (300MHz, CDCl
3) δ 3.58-3.70 (br s, 1H); (2.98-3.09 m, 4H); (2.88-2.94 m, 2H); (2.82-2.87 m, 2H); (1.91 s, 2H); (1.46 s, 6H); (0.81 s, 9H); MS:ESI (cation): 300 (M+H); (C)
1H NMR (300MHz, CDCl
3) δ 6.75 (s, 1H); (2.92-3.11 m, 6H); (2.85-2.90 m, 2H); (2.72-2.82 br s, 1H); MS:ESI (cation): 188 (M+H).
Embodiment 49.
2-bromo-5,6,7,8-tetrahydrochysene-4H-furo [2,3-d] azepine(flow process 11)
A.) furan-2-base-oxo-acetic acids ethyl ester:
To be dissolved in CHCl
3Furan (420ml)-2-base-oxo-acetic acids (15g, 107mmol) EtOH (9.6ml, 165mmol) and H
2SO
4(1ml) process, and be heated to 63 ℃ of maintenances 12 hours.Then, reactant mixture is transferred in separatory funnel, used saturated NaHCO
3(100ml) washing.Organic layer is washed dry (MgSO with saline (100ml)
4), concentrated, obtain the above-mentioned subtitle compounds of 16.9g (66%), it uses in following steps without being further purified namely.
B.) furan-2-base-hydroxyl-acetic acid:
With step a.) EtOH (250ml) solution of product (25g, 135mmol) is cooled to 0 ℃, uses NaBH
4The H of (2.5g, 66mmol)
2O (27ml) solution-treated 5 minutes.Then, with reactant mixture AcOH (17ml) and H
2O (271ml) quencher is concentrated into dried.Thick oil is dissolved in CH
2Cl
2(300ml), with saline (2 * 100ml) washings, dry (MgSO
4), concentrated, obtain the above-mentioned subtitle compounds of 17.5g (70%), it uses in following steps without being further purified namely.
C.) (3-carboxymethyl furan-2-yl)-acetic acid:
With step b.) naphthalane (193ml) solution of product (10.9g, 64mmol) is with trimethyl orthoacetate (48.2ml, 384mmol) and caproic acid (2.0ml) processing.Then, reactant mixture is packed in Vigreux column, be heated to 180 ℃ and kept 18 hours.At front 6 hours of the response time, added the caproic acid (3 * 1.5ml) of equal portions every 2 hours.Then, reactant is cooled to 22 ℃, with the MeOH extraction, obtains the crude mixture of 27g diester and naphthalane.This mixture is dissolved in MeOH (250ml), is cooled to 0 ℃, process with 2M NaOH (150ml).After 12 hours, evaporating solvent absorbs residue in 2N NaOH (100ml), with ether (2 * 150ml) washings.Alkaline layer is acidified to pH 1 with 4M HCl, and (4 * 100ml) strip with EtOAc.With organic layer salt water washing, dry (MgSO
4), concentrated, obtain the above-mentioned subtitle compounds of 6.4g (54%).
D.) 2-[3-(2-ethoxy)-furan-2-yl]-ethanol:
With step c) anhydrous THF (400ml) solution of product (6.4g, 35mmol) is cooled to 0 ℃, drips 1.0M BH in 10 minutes
3THF (174ml, 174mmol) solution.After dropwising, mixture was stirred under 0 ℃ 20 minutes again, then be warming up to 22 ℃ and kept 2 hours.Then, mixture is poured into ice-cold saturated NaHCO
3(300ml), with EtOAc (2 * 200ml) extractions.With the dry (MgSO of organic layer
4), concentrated, obtain 3.58g (65%) subtitle compounds.MS:ESI (cation): 157 (M+H).
E.) methanesulfonic acid 2-[3-(2-mesyloxy ethyl)-furan-2-yl] ethyl ester:
With steps d .) CH of product (3.58g, 22.9mmol)
2Cl
2(114ml) solution is cooled to 0 ℃, processes with triethylamine (9.56ml, 68.7mmol), then drips mesyl chloride (3.88ml, 50.4mmol) in 10 minutes.After 1 hour, reactant mixture is transferred in separatory funnel, with frozen water (1 * 50ml), 10% citric acid (2 * 50ml), saturated NaHCO
3(2 * 50ml) and saline (1 * 50ml) extraction.With the dry (MgSO of organic layer
4), be concentrated into 20ml, with anhydrous dioxane (42ml) dilution, reconcentration is to remove remaining CH
2Cl
2The dioxane solution of the dimethanesulfonate of gained is used for step f immediately).
F.) 6-benzyl-5,6,7,8-tetrahydrochysene-4H-furo [2,3-d] azepine:
With step e) after the dioxane solution of the dimethanesulfonate that produces dilutes with anhydrous dioxane (168ml), transfer in the 3 neck reaction flasks that Dropping funnel and condenser are housed.Add anhydrous K
2CO
3(46.5g, 337mmol) is with mixture heated to 102 ℃.Then, drip dioxane (74.4ml) solution of benzylamine (7.5g, 70.1mmol) in 45 minutes, continued back flow reaction 18 hours.Reactant is cooled to 22 ℃, salt is leached, evaporating solvent.Thick oil obtains 2.56g (49%) (step e) and merging productive rate f) by silica gel column chromatography (EtOAc/ hexane gradient) purification) subtitle compounds.MS:ESI (cation): 228 (M+H).
G.) 5,6,7,8-tetrahydrochysene-4H-furo [2,3-d] azepine hydrochlorate:
With step f) anhydrous dichloroethanes (56ml) solution of product (2.56mg, 11.3mmol) is cooled to 0 ℃, processes with chloro-carbonic acid 1-chloroethene ester (6.11ml, 56.4mmol), and then reactant is warming up to 22 ℃ and kept 1 hour.With reactant CH
2Cl
2(100ml) dilution, use saturated NaHCO
3(50ml) washing.With saturated NaHCO
3Use CH
2Cl
2Strip, the organic layer of merging washs with saline (50ml), dry (MgSO
4), concentrated, obtain the oily residue, it is absorbed in anhydrous MeOH (150ml), refluxed 1 hour.Evaporation MeOH, crude product grinds with ether, filters, and obtains 1.71g (87%) subtitle compounds.
1H NMR (300MHz, DMSO) δ 9.56 (br s, 2H); (7.43 d, J=2Hz, 1H); (6.34 d, J=2Hz, 1H); (3.18-3.30 br m, 4H); (3.03-3.10 br m, 2H); (2.74-2.82 br m, 2H); MS:ESI (cation): 138 (M+H).
H.) 4,5,7,8-tetrahydrochysene-furo [2,3-d] azepine-6-t-butyl formate:
With step g) acetone (7.2ml) and water (7.2ml) the solution NaHCO of product (500mg, 2.88mmol)
3(484mg, 5.76mmol) and Bis(tert-butoxycarbonyl)oxide (691mg, 3.17mmol) were processed 1 hour under vigorous stirring.With content H
2O (10ml) dilution is with EtOAc (2 * 50ml) extractions.With the dry (MgSO of organic layer
4), concentrated, through chromatography (EtOAc/ hexane gradient) purification, obtain 643mg (94%) subtitle compounds.MS:ESI (cation): 238 (M+H).
I.) the 2-bromo-5,6,7,8-tetrahydrochysene-4H-furo [2,3-d] azepine:
With step h) CHCl of product (50mg, 0.21mmol)
3(527 μ l) and AcOH (527 μ l) solution is processed with N-bromosuccinimide (38.1mg, 0.21mmol) under 22 ℃.After 1 hour, pour content into saturated NaHCO
3In, with EtOAc (2 * 5ml) extractions.(1 * 5ml) washs, dry (MgSO with saline with organic layer
4), through preparation type TLC (80% hexane: 20%EtOAc) purification, obtain 2-bromo-4,5,7,8-tetrahydrochysene-furo [2,3-d] azepine-6-t-butyl formate, its dioxane with 4M HCl (2ml) solution is directly processed.The evaporation dioxane, residue is dissolved in MeOH, through preparation type LC/MS purification, obtains the 1.3mg title compound.
1H NMR (CDCl
3) 6.08 (s, 1H); (3.02-3.07 m, 4H); (2.89-2.92 m, 2H); (2.57-2.70 m, 3H); MS:ESI (cation): 216,218 (M+H).
Assess as 5HT with following methods
2cThe representative compound of the present invention of receptor stimulating agent.The result of this test provides in table 1.
Cell culture
VNV isotype: will express people 5HT
2cThe HEK 293EBNA of receptor (Burns etc., NATURE 387:30308,1997) in the DMEM that contains 10% dialysis FBS, 9 μ g/ml blasticidins at 37 ℃, 5%CO
2Cultivate under atmosphere.
The calcium mobilization
To express people 5HT
2cThe HEK 293EBNA cell (2 * 10 of receptor
4/ hole) be inoculated on the 384-hole collagen coated board of black, at 37 ℃, 5%CO
2Be incubated overnight under/95% air.After removing culture medium, cell is with HBSS buffer (the 137mM NaCl that contains Calcium3 dyestuff (Molecular Device, CA), 2.5mM probenecid and 0.08%pluronic acid, 5.4 mM KCl, 5.5mM glucose, 20mM Hepes, pH7.5,2.1mM MgCl
2, 0.3mM CaCl
2, 0.02mM MgSO
4, 3.0mM NaHCO
3With 0.64mM KH
2PO
4) processed 60 minutes according to manufacturers instruction.With diluted chemical compound in CsCl Ringers buffer (58.3mM CsCl, 5.4mM KCl, 5.5mM glucose, 20mM Hepes, pH7.5,2.1mMMgCl
2, 1.2mM CaCl
2) in.5HT is as positive control.Read at fluorescence imaging calcium release and the consequential fluorescence that the upper measurement of plate device (FLIPR, Molecular Device, CA) part is induced.
Data analysis
All data are all analyzed with the non-linear least square curve fitting with Prism 4.0 softwares.With equation Y=bottom+(top-bottom)/(1+10^ ((LogEC50-X))), wherein X is the logarithm of compound concentration, Y is fluorescence reaction, and agonist in FLIPR is fitted to S shape dose-effect curve to the stimulation of calcium induced fluorescence.
Table 1
Claims (5)
1. the compound of a following formula or the acceptable salt of its medicine:
X is O or S;
R
1Be selected from halogen, C
1-8Alkyl, OR
5And SO
2N(R
5)
2
R
2Be selected from hydrogen, halogen, C
1-8Alkyl and OR
5, perhaps with R
3Form together 5 rings;
R
3Hydrogen or C
1-8Alkyl;
R
3aHydrogen;
R
4Hydrogen or C
1-8Alkyl;
R
4aHydrogen; With
R
5Hydrogen or C
1-8Alkyl.
2. compound, described compound is selected from:
1) the 2-bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2) the 2-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
3) 2,3-two bromo-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
4) 2,3-two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
5) 2-bromo-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
6) 2-chloro-4-methoxy-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
7) 2-chloro-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
8) 2,3-two chloro-4-methyl-5,6,7,8-tetrahydrochysene-thieno [2,3-d] azepine;
9) 2-(4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
10) 2-(2,5-difluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
11) 2-(3-chloro-4-fluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
12) 2-(2,5-Dichlorobenzene base)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
13) 2-(5-fluoro-2-methoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
14) 2-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
15) 2-(4-ethoxyl phenenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
16) 2-(4-ethylphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
17) 2-(3-methoxyphenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
18) 2-phenyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
19) 2-naphthalene-1-base-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
20) 2-naphthalene-2-base-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
21) 2-(2,6-difluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
22) 3-(2,6-difluorophenyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
23) 2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
24) 3-bromo-2-(2-chloro-6-luorobenzyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
25) 2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
26) 2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
27) 2-bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
28) 2-bromo-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
29) N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
30) N, N-dimethyl-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
31) the 2-bromo-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
32) 2-methyl-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
33) 2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
34) 3-bromo-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine; With
35) the 2-tert-butyl group-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine, or the acceptable salt of its medicine.
3. compound, described compound is selected from:
1) 2,3-two chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2) 2-bromo-3-chloro-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
3) 2-bromo-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
4) 2-bromo-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
5) 2-bromo-4-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
6) 2-bromo-8-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
7) N, N-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
8) N, N-dimethyl-3-methyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-sulfonamide;
9) the 2-bromo-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
10) 2-methyl-4,4a, 5,6,7,8-, six hydrogen-3H-1-thia-6-azepine-cyclopenta [cd] azulene;
11) 2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
12) 3-bromo-2-trifluoromethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine; With
13) the 2-tert-butyl group-3-methoxyl group-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine, or the acceptable salt of its medicine.
4. pharmaceutical composition, described pharmaceutical composition comprises compound and the medicine acceptable carrier of any one at least a claim 1-3.
5. compound, it is selected from
2-(4-Trifluoromethoxyphen-l)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2-(2-trifluoromethyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2-(pyrrolidine-1-sulfonyl)-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
2-bromo-8-Spirocyclopropyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine;
5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine-2-formic acid ring pentanamide; With
2-bromo-8,8-dimethyl-5,6,7,8-tetrahydrochysene-4H-thieno [2,3-d] azepine; Or the acceptable salt of its medicine.
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ZA821020B (en) * | 1981-02-18 | 1983-10-26 | Thomae Gmbh Dr K | Azepine derivatives, process for their preparation and pharmaceutical compositions thereof |
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WO2002074746A1 (en) * | 2001-03-16 | 2002-09-26 | Yamanouchi Pharmaceutical Co., Ltd. | Benzazepine derivatives |
JP2003261566A (en) * | 2002-03-11 | 2003-09-19 | Sankyo Co Ltd | Medicament containing quinolizine |
US7452911B2 (en) * | 2002-10-31 | 2008-11-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Alkyne compounds with MCH antagonistic activity and medicaments comprising these compounds |
SG146683A1 (en) | 2003-09-17 | 2008-10-30 | Janssen Pharmaceutica Nv | Fused heterocyclic compounds as serotonin receptor modulators |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0488663A1 (en) * | 1990-11-28 | 1992-06-03 | Lilly Industries Limited | Pyrrolo[2,3-d]azepine derivatives, process for their preparation and pharmaceutical compositions containing them |
Non-Patent Citations (1)
Title |
---|
Sanofi Recherche等.New synthesis of 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepine.Journal of heterocyclic chemistry22.1985,22第1011-1016页. * |
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JP2008505101A (en) | 2008-02-21 |
WO2006004931A2 (en) | 2006-01-12 |
CN1980710A (en) | 2007-06-13 |
US7718647B2 (en) | 2010-05-18 |
EP1778243A2 (en) | 2007-05-02 |
US20100190772A1 (en) | 2010-07-29 |
CY1113559T1 (en) | 2016-06-22 |
AU2005260636A1 (en) | 2006-01-12 |
ZA200609234B (en) | 2008-08-27 |
RU2485125C2 (en) | 2013-06-20 |
CA2565683A1 (en) | 2006-01-12 |
US20060003990A1 (en) | 2006-01-05 |
NO20070494L (en) | 2007-03-23 |
KR20070041544A (en) | 2007-04-18 |
KR101216984B1 (en) | 2013-01-02 |
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EP1778243A4 (en) | 2009-09-30 |
TWI358410B (en) | 2012-02-21 |
TW200611906A (en) | 2006-04-16 |
IL179278A0 (en) | 2007-03-08 |
AR049954A1 (en) | 2006-09-20 |
JP5025469B2 (en) | 2012-09-12 |
BRPI0512742A (en) | 2008-04-15 |
DK1778243T3 (en) | 2013-02-04 |
RU2007103465A (en) | 2008-08-10 |
ES2398694T3 (en) | 2013-03-21 |
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IL179278A (en) | 2014-11-30 |
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